Substituted nicotinimide inhibitors of BTK and their preparation and use in the treatment of cancer, inflammation and autoimmune disease

ABSTRACT

Compounds of Formula I, as shown below and defined herein: 
     
       
         
         
             
             
         
       
         
         
           
             and pharmaceutically acceptable salts, syntheses, intermediates, formulations, and methods of treating diseases including cancer, inflammation, and autoimmune disease mediated at least in part by Bruton&#39;s Tyrosine Kinase (BTK).

This application is a continuation of U.S. application Ser. No.15/025,654, filed Mar. 30, 2016; which is a 371 national phaseapplication of PCT/US2014/058084, filed Sep. 29, 2014; which claimspriority under 35 U.S.C. 119(e) to U.S. Provisional Patent ApplicationNo. 61/884,958, filed on Sep. 30, 2013, and under 35 U.S.C. 119(a) toChinese Patent Application No. 201310485048.1, filed on Oct. 16, 2013,The entire contents of each of the above-referenced applications areincorporated herein by reference.

FIELD AND BACKGROUND

The present invention relates to chemical compounds, pharmaceuticalcompositions including these compounds, and their use in treatment ofdisease. In particular, the present invention relates to the use ofsubstituted nicotinimides as irreversible inhibitors of tyrosine kinasesuseful in the treatment of diseases mediated by Bruton's Tyrosine Kinase(BTK) including cancer, inflammation and autoimmune disease.

BTK is a Tec family non-receptor protein kinase which plays a role inmultiple signal-transduction pathways regulating survival, activation,proliferation, and differentiation of B-lineage lymphoid cells. BTK isoverexpressed and active in several B-lineage lymphoid malignancies. BTKis expressed in malignant cells in humans with B-Cell Precursor(BCP)-Acute Lymphoblastic Leukemia (ALL), Chronic Lymphocytic Leukemia(CLL), and Non-Hodgkin's Lymphoma (NHL). BTK is an upstream activator ofanti-apoptotic signaling molecules and networks, including: SignalTransducer and Activator of Transcription 5 (STATS) protein,Phosphatidylinositol (PI), 3-kinase/AKT/Mammalian Target of Rapamycin(mTOR) pathway, and Nuclear Factor kappa B (NF-κB). D'Cruz, Osmond J.,OncoTargets and Therapy 2013: 6, 161-176.

PCT/CN2012/000971 to De Man et al. describes that BTK is expressed in Bcells and myeloid cells, and is a terminal enzyme in the B-Cell antigenReceptor (BCR) signaling pathway. Mutations in human BTK leads toX-Linked Agammaglobulinemia (XLA), an immunodeficiency disease relatedto a failure to generate mature B cells leading to reducedimmunoglobulin in serum. BTK is therefore implicated in regulation ofthe production of autoantibodies in autoimmune diseases. Furthermore,BTK may play a role in treatment of autoimmune diseases characterized byproduction of pro-inflammatory cytokines and chemokines by B cells dueto BTK's position in the BCR pathway. BTK inhibitors may be used fortreatment of B cell lymphomas due to BTK's involvement in the regulationof proliferation and apoptosis of B cells. Inhibition of BTK is relevantin particular for B cell lymphomas due to chronic active BCR signaling.Davis et al., Nature, 463 (2010), 88-94.

Adaptive immune responses may involve B lymphocyte activation andabsence of B lymphocyte activation is an indication of autoimmunedisease. Treatment of autoimmune disease, such as Rheumatoid Arthritis(RA), with Rituximab, an anti-CD20 therapy, demonstrates that B celltherapies are effective. Additionally, treatment with Rituximab has beenshown to improve disease symptoms in Relapsing Remitting MultipleSclerosis (RRMS) and Systemic Lupus Erythematosus (SLE) patients.Accordingly, targeting B cell immunity is effective for treatment ofautoimmune diseases.

SUMMARY

The present invention includes certain substituted compounds describedherein, their pharmaceutically acceptable salts, solvates and hydrates,preparation of the compounds, intermediates, pharmaceutical compositionsand formulations thereof, and methods of treating disease includingcancers, inflammation, and autoimmune diseases therewith.

The present invention includes compounds of Formula I andpharmaceutically acceptable salts thereof as provided below and furtherdefined herein:

In some aspects, compounds of the invention are irreversible inhibitorsof kinases, including Bruton's Tyrosine Kinase (BTK). In some aspects,compounds of the invention are selective inhibitors of BTK.

In some aspects, the invention includes methods of treatingproliferative disease, particularly cancers, conditions causinginflammation, and autoimmune diseases mediated at least in part by BTK,alone or in combination regimens with other therapies.

Compounds of the present invention, and pharmaceutically acceptablecompositions thereof, are useful as inhibitors of protein kinases. Insome embodiments, the compounds are effective as inhibitors of Bruton'sTyrosine Kinase (BTK). In some aspects, the invention includespharmaceutically acceptable salts of the compounds of Formula I:

wherein:

A is selected from C₃₋₁₂cycloalkyl, C₃₋₁₂heterocycloalkyl, C₃₋₁₂aryl, orC₃₋₁₂heteroaryl, any of which is optionally substituted with G¹substituents;

B¹ is selected from C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-,C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-, aryl-C₀₋₁₂alkyl-,aryl-C₃₋₁₂cycloalkyl-, aryl-C₃₋₁₂heterocycloalkyl-,heteroaryl-C₀₋₁₂alkyl-, heteroaryl-C₃₋₁₂cycloalkyl-, orheteroaryl-C₃₋₁₂heterocycloalkyl-, any of which is optionallysubstituted with G² substituents;

B² is selected from C₀₋₁₂alkyl, C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-,C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-, aryl-C₀₋₁₂alkyl-,aryl-C₃₋₁₂cycloalkyl-, aryl-C₃₋₁₂heterocycloalkyl-,heteroaryl-C₀₋₁₂alkyl-, heteroaryl-C₃₋₁₂cycloalkyl-, orheteroaryl-C₃₋₁₂heterocycloalkyl-, any of which is optionallysubstituted with G³ substituents;

L¹ is selected from —C₀₋₁₂alkyl-, —CR⁵R⁶—, —C₀₋₃alkyl(R⁵)(OH)—, —C(O)—,—CH₂O—, —OCH₂—, —CF₂—, —SCR⁵R⁶—, —CR⁵R⁶S—, —N(R⁵)—, —N(R⁵)C(O)—,—C(O)N(R⁵)—, —N(R⁵)C(O)N(R⁶)—, —O—, —S—, —S(O)_(m1)—, —N(R⁵)S(O)_(m1)—,or —S(O)_(m1)N(R⁵)—;

L² is selected from —C₀₋₄alkyl-, —C(O)—, —N(R⁷)—, —N(R⁷)C(O)—, or—N(R⁷)S(O)_(m2)—;

X is selected from C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-,C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-, aryl-C₀₋₁₂alkyl-,aryl-C₃₋₁₂cycloalkyl-, aryl-C₃₋₁₂heterocycloalkyl-,heteroaryl-C₀₋₁₂alkyl-, heteroaryl-C₃₋₁₂cycloalkyl-, orheteroaryl-C₃₋₁₂heterocycloalkyl-, any of which is optionallysubstituted with G⁴ substituents;

Y is selected from —C(O)—, —N(R⁸)—, —N(R⁸)C(O)—, —S(O)_(m3)—, or—N(R⁸)S(O)_(m3)—;

R¹ is selected from —C(O)R⁹, —C(O)NR⁹R¹⁰, —C(O)OR⁹, C₁₋₄alkynyl, OR⁹,S(O)_(m4)R⁹R¹⁰, or —CN;

R², R³, and R⁴ are each independently selected from C₀₋₁₂alkyl, —CN,halo, C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-, C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-,aryl-C₀₋₁₂alkyl-, aryl-C₃₋₁₂cycloalkyl-, aryl-C₃₋₁₂heterocycloalkyl-,heteroaryl-C₀₋₁₂alkyl-, heteroaryl-C₃₋₁₂cycloalkyl-, orheteroaryl-C₃₋₁₂heterocycloalkyl-, any of which is optionallysubstituted with G⁵ substituents;

R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently selected fromC₀₋₁₂alkyl, C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-,C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-, aryl-C₀₋₁₂alkyl-,aryl-C₃₋₁₂cycloalkyl-, aryl-C₃₋₁₂heterocycloalkyl-,heteroaryl-C₀₋₁₂alkyl-, heteroaryl-C₃₋₁₂cycloalkyl-, orheteroaryl-C₃₋₁₂heterocycloalkyl-, any of which is optionallysubstituted with G⁶ substituents;

G¹, G², G³, G⁴, G⁵, and G⁶ are each independently selected from one ormore of C₀₋₁₂alkyl, —C₂₋₁₂alkenyl, —C₂₋₁₂alkynyl, D, —CD₃, —OCD₃, halo,—CN, -oxo-, —CF₃, —OCF₃, —OCHF₂, —NO₂, —B(OH)₂, —P(O)C₀₋₃alkyl,—PO(OR¹¹)₂, —PO(OR¹¹)R¹², C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-,C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-, aryl-C₀₋₁₂alkyl-,aryl-C₃₋₁₂cycloalkyl-, aryl-C₃₋₁₂heterocycloalkyl-,heteroaryl-C₀₋₁₂alkyl-, heteroaryl-C₃₋₁₂cycloalkyl-,heteroaryl-C₃₋₁₂heterocycloalkyl-, —C₀₋₆alkylOR¹¹, —OC(O)NR¹¹R¹²,—C(O)OR¹¹, —C(O)NR¹¹R¹², —C(O)R¹¹, —NR¹¹R¹², —NR¹¹C(O)R¹²,—NR¹³C(O)NR¹¹R¹², —S(O)_(m5)R¹¹, and —NR¹¹S(O)_(m5)R¹², any of which isoptionally substituted with Q¹ substituents;

Q¹ is selected from one or more of C₀₋₁₂alkyl-, —C₂₋₁₂alkenyl,—C₂₋₁₂alkynyl, D, halo, —CN, —CD₃, —OCD₃, -oxo-, —CF₃, —OCF₃, —OCHF₂,—NO₂, —B(OH)₂, —PO(OR¹⁴)₂, —PO(OR¹⁴)R¹⁵, NR¹⁴R¹⁵, —C(O)NR¹⁴OH,—C₀₋₆alkylOR¹⁴, aryl-C₀₋₁₂alkyl-, heteroaryl-C₀₋₁₂alkyl-,C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-, C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-,aryl-C₀₋₁₂cycloalkyl-, heteroaryl-C₃₋₁₂cycloalkyl-,C₁₋₁₂heterocycloalkyl-C₃₋₁₂cycloalkyl-,C₃₋₁₂cycloalkyl-C₃₋₁₂cycloalkyl-,C₃₋₁₂heterocycloalkyl-C₃₋₁₂heterocycloalkyl-,aryl-C₃₋₁₂heterocycloalkyl-, heteroaryl-C₃₋₁₂heterocycloalkyl-,—C(O)—C(O)NR¹⁴R¹⁵, —C(O)—C(O)OR¹⁴, —OC(O)R¹⁴, —NR¹⁴C(O)R¹⁵,—NR¹⁴S(O)_(m6)R¹⁵, —(CR¹⁵R¹⁶)_(n1)C(O)R¹⁴, —(CR¹⁵R¹⁶)_(n1)C(O)OR¹⁴,—(CR¹⁵R¹⁶)_(n1)C(O)NR¹⁴R¹⁷, —(CR¹⁵R¹⁶)_(n1)S(O)_(m6)NR¹⁴R¹⁷,—(CR¹⁵R¹⁶)_(n1)NR¹⁴R¹⁷, —(CR¹⁵R¹⁶)_(n1)OR¹⁴,—(CR¹⁵R¹⁶)_(n1)S(O)_(m6)R¹⁴, —NR¹⁶C(O)NR¹⁴R¹⁵, and—NR¹⁶S(O)_(m6)NR¹⁴R¹⁵, any of which is optionally substituted withindependently selected E¹ substituents;

E¹ is selected from one or more of C₀₋₁₂alkyl-, —C₂₋₁₂alkenyl,—C₂₋₁₂alkynyl, D, halo, —CN, -oxo-, —CD₃, —OCD₃, —CF₃, —OCF₃, —OCHF₂,—NO₂, —B(OH)₂, —PO(OR¹⁸)₂, —PO(OR¹⁸)R¹⁹, —C(O)N¹⁸OH, —C(O)NR¹⁸R¹⁹,—C₀₋₁₂alkylOR¹⁸, aryl-C₀₋₁₂alkyl-, heteroaryl-C₀₋₁₂alkyl-,C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-, C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-,aryl-C₀₋₁₂cycloalkyl-, heteroaryl-C₃₋₁₂cycloalkyl-,C₃₋₁₂heterocycloalkyl-C₃₋₁₂cycloalkyl-,C₃₋₁₂cycloalkyl-C₃₋₁₂cycloalkyl-,C₃₋₁₂heterocycloalkyl-C₃₋₁₂heterocycloalkyl-,aryl-C₃₋₁₂heterocycloalkyl-, heteroaryl-C₃₋₁₂heterocycloalkyl-,—C(O)—C(O)NR¹⁸R¹⁹, —C₀₋₁₂alkylC(O)OR¹⁸, —C(O)—C(O)OR¹⁸, —OC(O)R¹⁸,—NR¹⁸C(O)R¹⁹, —NR¹⁸C(O)OR¹⁹, —NR¹⁸S(O)_(m7)R¹⁹, —(CR¹⁹R²⁰)_(n2)C(O)R¹⁸,—(CR¹⁹R²⁰)_(n2)C(O)OR¹⁸, —(CR¹⁹R²⁰)_(n2)C(O)NR¹⁸R²¹,—(CR¹⁹R²⁰)_(n2)S(O)_(m7)NR¹⁸R²¹, (CR¹⁹R²¹)_(n2)NR¹⁸R²¹,—(CR¹⁹R²⁰)_(n2)OR¹⁸, —(CR¹⁹R²⁰)_(n2)S(O)_(m7)R¹⁸, —NR²⁰C(O)NR¹⁸R¹⁹, and—NR²⁰S(O)_(m7)NR¹⁸R¹⁹ substituents;

R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, and R²¹ are eachindependently selected from H, C₁₋₆alkyl-, C₃₋₆cycloalkyl-C₀₋₆alkyl-,C₃₋₆heterocycloalkyl-C₀₋₆alkyl-, aryl-C₀₋₆alkyl-, aryl-C₃₋₈cycloalkyl-,aryl-C₃₋₈heterocycloalkyl-, heteroaryl-C₁₋₆alkyl-,heteroaryl-C₃₋₈cycloalkyl-, or heteroaryl-C₃₋₆heterocycloalkyl-;

R³ and R⁴ are taken together with the carbon atoms to which they areattached to form a 3-12 membered partially saturated or unsaturatedring, wherein said ring optionally includes one or more additionalheteroatoms selected from O, N, or S(O)_(m8);

m1, m2, m3, m4, m5, m6, m7, m8, n1, and n2 are each independentlyselected from 0, 1, or 2;

or a pharmaceutically acceptable salt, solvate or a prodrug thereof.

In some aspects of Formula I, compounds of the present invention are asubgenus of Formula I, having the Formula Ia:

wherein:

B¹ is selected from C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-,C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-, aryl-C₀₋₁₂alkyl-,aryl-C₃₋₁₂cycloalkyl-, aryl-C₃₋₁₂heterocycloalkyl-,heteroaryl-C₀₋₁₂alkyl-, heteroaryl-C₃₋₁₂cycloalkyl-, orheteroaryl-C₃₋₁₂heterocycloalkyl-, any of which is optionallysubstituted with G² substituents;

B² is selected from C₀₋₁₂alkyl, C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-,C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-, aryl-C₀₋₁₂alkyl-,aryl-C₃₋₁₂cycloalkyl-, aryl-C₃₋₁₂heterocycloalkyl-,heteroaryl-C₀₋₁₂alkyl-, heteroaryl-C₃₋₁₂cycloalkyl-, orheteroaryl-C₃₋₁₂heterocycloalkyl-, any of which is optionallysubstituted with G³ substituents;

L¹ is selected from —C₀₋₂alkyl-, —CR⁵R⁶—, —C₀₋₃alkyl(R⁵)(OH)—, —C(O)—,—CH₂O—, —OCH₂—, —CF₂—, —SCR⁵R⁶—, —CR⁵R⁶S—, —N(R⁵)—, —N(R⁵)C(O)—,—C(O)N(R⁵)—, —N(R⁵)C(O)N(R⁶)—, —O—, —S—, —S(O)_(m1)—, —N(R⁵)S(O)_(m1)—,or —S(O)_(m1)N(R⁵)—;

L² is selected from —C₀₋₄alkyl-, —C(O)—, —N(R⁷)—, —N(R⁷)C(O)⁻, or—N(R⁷)S(O)_(m2)—;

X is selected from C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-,C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-, aryl-C₀₋₁₂alkyl-,aryl-C₃₋₁₂cycloalkyl-, aryl-C₃₋₁₂heterocycloalkyl-,heteroaryl-C₀₋₁₂alkyl-, heteroaryl-C₃₋₁₂cycloalkyl-, orheteroaryl-C₃₋₁₂heterocycloalkyl-, any of which is optionallysubstituted with G⁴ substituents;

Y is selected from —C(O)—, —N(R⁸)—, —N(R⁸)C(O)—, —S(O)_(m3)—, or—N(R⁸)S(O)_(m3)—;

Z¹ is (CR^(a))₀₋₁;

Z² is selected from CR^(b), NR^(b), O, or S;

Z³ is selected from C or N;

Z⁴ is selected from CR^(c), NR^(c), O, or S;

R¹ is selected from —C(O)R⁹, —C(O)NR⁹R¹⁰, —C(O)OR⁹, C₁₋₄alkynyl, OR⁹,S(O)_(m4)R⁹R¹⁰, or —CN;

R², R³, R⁴, R³, R^(b), and R^(c) are each independently selected fromC₀₋₁₂alkyl, —CN, halo, C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-,C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-, aryl-C₀₋₁₂alkyl-,aryl-C₃₋₁₂cycloalkyl-, aryl-C₃₋₁₂heterocycloalkyl-,heteroaryl-C₀₋₁₂alkyl-, heteroaryl-C₃₋₁₂cycloalkyl-, orheteroaryl-C₃₋₁₂heterocycloalkyl-, any of which is optionallysubstituted with G⁵ substituents;

R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently selected fromC₀₋₁₂alkyl. C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-,C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-, aryl-C₀₋₁₂alkyl-,aryl-C₃₋₁₂cycloalkyl-, aryl-C₃₋₁₂heterocycloalkyl-,heteroaryl-C₀₋₁₂alkyl-, heteroaryl-C₃₋₁₂cycloalkyl-, orheteroaryl-C₃₋₁₂heterocycloalkyl-, any of which is optionallysubstituted with G⁶ substituents;

G¹, G², G³, G⁴, G¹, and G⁶ are each independently selected from one ormore of C₀₋₁₂alkyl, —C₂₋₁₂alkenyl, —C₂₋₁₂alkynyl, D, —CD₃, —OCD₃, halo,—CN, -oxo-, —CF₃, —OCF₃, —OCHF₂, —NO₂, —B(OH)₂, —P(O)C₀₋₃alkyl,—PO(OR¹¹)₂, —PO(OR¹¹)R¹², C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-,C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-, aryl-C₀₋₁₂alkyl-,aryl-C₃₋₁₂cycloalkyl-, aryl-C₃₋₁₂heterocycloalkyl-,heteroaryl-C₀₋₁₂alkyl-, heteroaryl-C₃₋₁₂cycloalkyl-,heteroaryl-C₃₋₁₂heterocycloalkyl-, —C₀₋₆alkylOR¹¹, —OC(O)NR¹¹R¹²,—C(O)OR¹¹, —C(O)NR¹¹R¹², —C(O)R¹¹, —NR¹¹R¹², —NR¹¹C(O)R¹²,—NR¹³C(O)NR¹¹R¹², —S(O)_(m5)R¹¹, and —NR¹¹S(O)_(m5)R¹², any of which isoptionally substituted with independently selected Q¹ substituents;

Q¹ is selected from one or more of C₀₋₁₂alkyl-, —C₂₋₁₂alkenyl,—C₂₋₁₂alkynyl, D, halo, —CN, —CD₃, —OCD₃, -oxo-, —CF₃, —OCF₃, —OCHF₂,—NO₂, —B(OH)₂, —PO(OR¹⁴)₂, —PO(OR¹⁴)R¹⁵, NR¹⁴R¹⁵, —C(O)NR¹⁴OH,—C₀₋₆alkylOR¹⁴, aryl-C₀₋₁₂alkyl-, heteroaryl-C₀₋₁₂alkyl-,C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-, C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-,aryl-C₀₋₁₂cycloalkyl-, heteroaryl-C₃₋₁₂cycloalkyl-,C₃₋₁₂heterocycloalkyl-C₃₋₁₂cycloalkyl-,C₃₋₁₂cycloalkyl-C₃₋₁₂cycloalkyl-,C₃₋₁₂heterocycloalkyl-C₃₋₁₂heterocycloalkyl-,aryl-C₃₋₁₂heterocycloalkyl-, heteroaryl-C₃₋₁₂heterocycloalkyl-,—C(O)—C(O)NR¹⁴R¹⁵, —C(O)—C(O)OR¹⁴, —OC(O)R¹⁴, —NR¹⁴C(O)R¹⁵,—NR¹⁴S(O)_(m6)R¹⁵, —(CR¹⁵R¹⁶)_(n1)C(O)R¹⁴, —(CR¹⁵R¹⁶)_(n1)C(O)OR¹⁴,—(CR¹⁵R¹⁶)_(n1)C(O)NR¹⁴R¹⁷, —(CR¹⁵R¹⁶)_(n1)S(O)_(m6)NR⁴R⁷,—(CR¹⁵R¹⁶)_(n1)NR¹⁴R¹⁷, —(CR¹⁵R¹⁶)_(n1)OR¹⁴,—(CR¹⁵R¹⁶)_(n1)S(O)_(m6)R¹⁴, —NR¹⁶C(O)NR¹⁴R¹⁵, and—NR¹⁶S(O)_(m6)NR¹⁴R¹⁵, any of which is optionally substituted withindependently selected E¹ substituents;

E¹ is selected from one or more of C₀₋₁₂alkyl-, —C₂₋₁₂alkenyl,—C₂₋₁₂alkynyl, D, halo, —CN, -oxo-, —CD₃, —OCD₃, —CF₃, —OCF₃, —OCHF₂,—NO₂, —B(OH)₂, —PO(OR¹⁸)₂, —PO(OR¹⁸)R¹⁹, —C(O)NR¹⁸OH, —C(O)NR¹⁸R¹⁹,—C₀₋₁₂alkylOR¹⁸, aryl-C₀₋₁₂alkyl-, heteroaryl-C₀₋₁₂alkyl-,C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-, C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-,aryl-C₀₋₁₂cycloalkyl-, heteroaryl-C₃₋₁₂cycloalkyl-,C₃₋₁₂heterocycloalkyl-C₃₋₁₂cycloalkyl-,C₃₋₁₂cycloalkyl-C₃₋₁₂cycloalkyl-,C₃₋₁₂heterocycloalkyl-C₃₋₁₂heterocycloalkyl-,aryl-C₃₋₁₂heterocycloalkyl-, heteroaryl-C₃₋₁₂heterocycloalkyl-,—C(O)—C(O)NR¹⁸R¹⁹, —C₀₋₁₂alkylC(O)OR¹⁸, —C(O)—C(O)OR¹⁸, —OC(O)R¹⁸,—NR¹⁸C(O)R¹⁹, —NR¹⁸C(O)OR¹⁹, —NR¹⁸S(O)_(m7)R¹⁹, —(CR¹⁹R²⁰)_(n2)C(O)R¹⁸.—(CR¹⁹R²⁰)_(n2)C(O)OR¹⁸, —(CR¹⁹R²⁰)_(n2)C(O)NR¹⁸R²¹,—(CR¹⁹R²⁰)_(n2)S(O)_(m7)NR¹⁸R²¹, —(CR¹⁹R²⁰)_(n2)NR¹⁸R²¹,(CR¹⁹R²⁰)_(n2)OR¹⁸, —(CR¹⁹R²⁰)_(n2)S(O)_(m7)R¹⁸, —NR²⁰C(O)NR¹⁸R¹⁹, and—NR²⁰S(O)_(m7)NR¹⁸R¹⁹ substituents;

R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, and R²¹ are eachindependently selected from H, C₁₋₆alkyl-, C₃₋₆cycloalkyl-C₀₋₆alkyl-,C₃₋₆heterocycloalkyl-C₀₋₆alkyl-, aryl-C₀₋₆alkyl-, aryl-C₃₋₈cycloalkyl-,aryl-C₃₋₈heterocycloalkyl-, heteroaryl-C₁₋₆alkyl-,heteroaryl-C₃₋₈cycloalkyl-, or heteroaryl-C₃₋₈heterocycloalkyl-;

R³ and R⁴ are taken together with the carbon atoms to which they areattached to form a 3-12 membered partially saturated or unsaturatedring, wherein said ring optionally includes one or more additionalheteroatoms selected from O, N, or S(O)_(m8);

m1, m2, m3, m4, m5, m6, m7, m8, n1, and n2 are each independentlyselected from 0, 1, or 2;

or a pharmaceutically acceptable salt, solvate or a prodrug thereof.

In some aspects of Formula I, compounds of the present invention are asubgenus of Formula I selected from one of Formulas Ib-Ii:

wherein:

B¹ is selected from C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-,C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-, aryl-C₀₋₁₂alkyl-,aryl-C₃₋₁₂cycloalkyl-, aryl-C₃₋₁₂heterocycloalkyl-,heteroaryl-C₀₋₁₂alkyl-, heteroaryl-C₃₋₁₂cycloalkyl-, orheteroaryl-C₃₋₁₂heterocycloalkyl-, any of which is optionallysubstituted with G² substituents;

B² is selected from C₀₋₁₂alkyl. C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-,C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-, aryl-C₀₋₁₂alkyl-,aryl-C₃₋₁₂cycloalkyl-, aryl-C₃₋₁₂heterocycloalkyl-,heteroaryl-C₀₋₁₂alkyl-, heteroaryl-C₃₋₁₂cycloalkyl-, orheteroaryl-C₃₋₁₂heterocycloalkyl-, any of which is optionallysubstituted with G³ substituents;

L¹ is selected from —C₀₋₁₂alkyl-, —CR⁵R⁶—, —C₀₋₃alkyl(R⁵)(OH)—, —C(O)—,—CH₂O—, —OCH₂—, —CF₂—, —SCR⁵R⁶—, —CR⁵R⁶S—, —N(R⁵)—, —N(R⁵)C(O)—,—C(O)N(R⁵)—, —N(R⁵)C(O)N(R⁶)—, —O—, —S—, —S(O)_(m1)—, —N(R⁵)S(O)_(m1)—,or —S(O)_(m1)N(R⁵)—;

L² is selected from —C₀₋₄alkyl-, —C(O)—, —N(R⁷)—, —N(R⁷)C(O)—, or—N(R⁷)S(O)_(m2)—;

X is selected from C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-,C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-, aryl-C₀₋₁₂alkyl-,aryl-C₃₋₁₂cycloalkyl-, aryl-C₃₋₁₂heterocycloalkyl-,heteroaryl-C₀₋₁₂alkyl-, heteroaryl-C₃₋₁₂cycloalkyl-, orheteroaryl-C₃₋₁₂heterocycloalkyl-, any of which is optionallysubstituted with G⁴ substituents;

Y is selected from —C(O)—, —N(R⁸)—, —N(R⁸)C(O)—, —S(O)_(m3)—, or—N(R⁸)S(O)_(m3)—;

R¹ is selected from —C(O)R⁹, —C(O)NR⁹R¹⁰, —C(O)OR⁹, C₁₋₄alkynyl, OR⁹,S(O)_(m4)R⁹R¹⁰, or —CN;

R², R³, and R⁴ are each independently selected from C₀₋₁₂alkyl, —CN,halo, C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-, C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-,aryl-C₀₋₁₂alkyl-, aryl-C₃₋₁₂cycloalkyl-, aryl-C₃₋₁₂heterocycloalkyl-,heteroaryl-C₀₋₁₂alkyl-, heteroaryl-C₃₋₁₂cycloalkyl-, orheteroaryl-C₃₋₁₂heterocycloalkyl-, any of which is optionallysubstituted with G⁵ substituents;

R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently selected fromC₀₋₁₂alkyl, C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-,C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-, aryl-C₀₋₁₂alkyl-,aryl-C₃₋₁₂cycloalkyl-, aryl-C₃₋₁₂heterocycloalkyl-,heteroaryl-C₀₋₁₂alkyl-, heteroaryl-C₃₋₁₂cycloalkyl-, orheteroaryl-C₃₋₁₂heterocycloalkyl-, any of which is optionallysubstituted with G⁶ substituents;

G¹, G², G³, G⁴, G⁵, and G⁶ are each independently selected from one ormore of C₀₋₁₂alkyl, —C₂₋₁₂alkenyl, —C₂₋₁₂alkynyl, D, —CD₃, —OCD₃, halo,—CN, -oxo-, —CF₃, —OCF₃, —OCHF₂, —NO₂, —B(OH)₂, —P(O)C₀₋₃alkyl,—PO(OR¹¹)₂, —PO(OR¹¹)R¹², C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-,C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-, aryl-C₀₋₁₂alkyl-,aryl-C₃₋₁₂cycloalkyl-, aryl-C₃₋₁₂heterocycloalkyl-,heteroaryl-C₀₋₁₂alkyl-, heteroaryl-C₃₋₁₂cycloalkyl-,heteroaryl-C₃₋₁₂heterocycloalkyl-, —C₀₋₆alkylOR¹¹, —OC(O)NR¹¹R¹²,—C(O)OR¹¹, —C(O)NR¹¹R¹², —C(O)R¹¹, —NR¹¹R¹², —NR¹¹C(O)R¹²,—NR¹³C(O)NR¹¹R¹², S(O)_(m5)R¹¹, and —NR¹¹S(O)_(m8)R¹², any of which isoptionally substituted with independently selected Q¹ substituents;

Q¹ is selected from one or more of C₀₋₁₂alkyl-, —C₂₋₁₂alkenyl,—C₂₋₁₂alkynyl, D, halo, —CN, —CD₃, —OCD₃, -oxo-, —CF₃, —OCF₃, —OCHF₂,—NO₂, —B(OH)₂, —PO(OR¹⁴)₂, —PO(OR¹⁴)R¹⁵, NR¹⁴R¹⁵, —C(O)NR¹⁴OH,—C₀₋₆alkylOR¹⁴, aryl-C₀₋₁₂alkyl-, heteroaryl-C₀₋₁₂alkyl-,C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-, C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-,aryl-C₀₋₁₂cycloalkyl-, heteroaryl-C₃₋₁₂cycloalkyl-,C₃₋₁₂heterocycloalkyl-C₃₋₁₂cycloalkyl-,C₃₋₁₂cycloalkyl-C₃₋₁₂cycloalkyl-,C₃₋₁₂heterocycloalkyl-C₃₋₁₂heterocycloalkyl-,aryl-C₃₋₁₂heterocycloalkyl-, heteroaryl-C₃₋₁₂heterocycloalkyl-,—C(O)—C(O)NR¹⁴R¹⁵, —C(O)—C(O)OR¹⁴, —OC(O)R¹⁴, —NR¹⁴C(O)R¹⁵,—NR¹⁴S(O)_(m6)R¹⁵, —(CR¹⁵R¹⁶)_(n1)C(O)R¹⁴, —(CR¹⁵R¹⁶)_(n1)C(O)OR¹⁴,—(CR¹⁵R¹⁶)_(n1)C(O)NR¹⁴R¹⁷, —(CR¹⁵R¹⁶)_(n1)S(O)_(m6)NR¹⁴R¹⁷,—(CR¹⁵R¹⁶)_(n1)NR¹⁴R¹⁷, —(CR¹⁵R¹⁶)_(n1)OR₁₄,—(CR¹⁵R¹⁶)_(n1)S(O)_(m6)R¹⁴, —NR¹⁶C(O)NR¹⁴R¹⁵, —NR¹⁶S(O)_(m6)NR¹⁴R¹⁵,any of which is optionally substituted with independently selected E¹substituents;

E¹ is selected from one or more of C₀₋₁₂alkyl-, —C₂₋₁₂alkenyl,—C₂₋₁₂alkynyl, D, halo, —CN, -oxo-, —CD₃, —OCD₃, —CF₃, —OCF₃, —OCHF₂,—NO₂, —B(OH)₂, —PO(OR⁸)₂, —PO(OR¹⁸)R¹⁹, —C(O)NR¹⁸OH, —C(O)NR¹⁸R¹⁹,—C₀₋₁₂alkylOR¹⁸, aryl-C₀₋₁₂alkyl-, heteroaryl-C₀₋₁₂alkyl-,C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-, C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-,aryl-C₀₋₁₂cycloalkyl-, heteroaryl-C₃₋₁₂cycloalkyl-,C₃₋₁₂heterocycloalkyl-C₃₋₁₂cycloalkyl-,C₃₋₁₂cycloalkyl-C₃₋₁₂cycloalkyl-,C₃₋₁₂heterocycloalkyl-C₃₋₁₂heterocycloalkyl-,aryl-C₃₋₁₂heterocycloalkyl-, heteroaryl-C₃₋₁₂heterocycloalkyl-,—C(O)—C(O)NR¹⁸R¹⁹, —C₀₋₁₂alkylC(O)OR¹⁸, —C(O)—C(O)OR¹⁸, —OC(O)R¹⁸,—NR¹⁵C(O)R¹⁹, —NR¹⁸C(O)OR⁹, —NR¹⁸S(O)_(m7)R¹⁹, —(CR¹⁹R²⁰)_(n2)C(O)R¹⁸,—(CR¹⁹R²⁰)_(n2)C(O)OR¹⁸, —(CR¹⁹R²⁰)_(n2)C(O)NR¹⁸R²¹,—(CR¹⁹R²⁰)_(n2)S(O)_(m7)NR¹⁸R²¹, —(CR¹⁹R²⁰)_(n2)NR¹⁸R²¹,—(CR¹⁹R²⁰)_(n2)OR¹⁸, —(CR¹⁹R²⁰)_(n2)S(O)_(m7)R¹⁸, —NR²⁰C(O)NR¹⁸R¹⁹, and—NR²⁰S(O)_(m7)NR⁸R⁹ substituents;

R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, and R²¹ are eachindependently selected from H, C₁₋₆alkyl-, C₃₋₆cycloalkyl-C₀₋₆alkyl-,C₃₋₆heterocycloalkyl-C₀₋₆alkyl-, aryl-C₀₋₆alkyl-, aryl-C₃₋₈cycloalkyl-,aryl-C₃₋₆heterocycloalkyl-, heteroaryl-C₁₋₆alkyl-,heteroaryl-C₃₋₈cycloalkyl-, or heteroaryl-C₃₋₆heterocycloalkyl-;

R³ and R⁴ are taken together with the carbon atoms to which they areattached to form a 3-12 membered partially saturated or unsaturatedring, wherein said ring optionally includes one or more additionalheteroatoms selected from O, N, or S(O)_(m8);

m1, m2, m3, m4, m5, m6, m7, m8, n1, and n2 are each independentlyselected from 0, 1, or 2;

or a pharmaceutically acceptable salt, solvate or a prodrug thereof.

In some embodiments of Formulas I, and Ia-Ii, B¹ is selected fromC₄₋₈cycloalkyl-C₀₋₁₂alkyl-, C₄₋₈heterocycloalkyl-C₀₋₁₂alkyl-,C₄₋₈aryl-C₀₋₁₂alkyl-, or C₄₋₈heteroaryl-C₀₋₁₂alkyl-, any of which isoptionally substituted with G² substituents.

In some embodiments of Formulas I, and Ia-Ii, B² is selected fromC₄₋₈cycloalkyl-C₀₋₁₂alkyl-, C₄₋₈heterocycloalkyl-C₀₋₁₂alkyl-,C₄₋₈aryl-C₀₋₂alkyl-, or C₄₋₈heteroaryl-C₀₋₁₂alkyl-, any of which isoptionally substituted with G³ substituents.

In some embodiments of Formulas I, and Ia-Ii, L¹ is selected from—C₀₋₂alkyl-, —CR⁵R⁶—, —C₀₋₃alkyl(R⁵)(OH)—, —C(O)—, —CH₂O—, —OCH₂—,—CF₂—, —N(R⁵)—, —N(R⁵)C(O)—, —C(O)N(R⁵)—, —O—, or —S(O)_(m1)—.

In some embodiments of Formulas I, and Ia-Ii, L¹ is selected from—C₀₋₂alkyl-, —CR⁵R⁶—, —C₁₋₂alkyl(R⁵)(OH)—, —C(O)—, —CF₂—, —N(R⁵)—,—N(R⁵)C(O)—, —C(O)N(R⁵)—, —O—, or —S(O)_(m1)—.

In some embodiments of Formulas I, and Ia-Ii, L² is selected from—C₀₋₂alkyl-, —C(O)—, or —N(R⁷)—.

In some embodiments of Formulas I, and Ia-Ii, X is selected fromC₄₋₈cycloalkyl-C₀₋₁₂alkyl-, C₄₋₈heterocycloalkyl-C₀₋₁₂alkyl-,C₄₋₈aryl-C₀₋₁₂alkyl-, or C₄₋₈heteroaryl-C₀₋₁₂alkyl-.

In some embodiments of Formulas I, and Ia-Ii, Y is selected from —C(O)—,—N(R)—, —N(R)C(O)—, or —S(O)_(m3)—.

In some embodiments of Formulas I, and Ia-Ii, R¹ is selected from—C(O)R⁹, —C(O)NR⁹R¹⁰, —C(O)OR⁹, C₁₋₄alkynyl, or —CN.

In some embodiments of Formulas I, and Ia-Ii, R², R³, and R⁴ are eachindependently selected from C₀₋₁₂alkyl, —CN, halo,C₃₋₆cycloalkyl-C₀₋₁₂alkyl-, C₃₋₆heterocycloalkyl-C₀₋₁₂alkyl-, any ofwhich is optionally substituted with G⁵ substituents.

In some embodiments of Formulas I, and Ia-Ii, G¹, G², G³, G⁴, G⁵, and G⁶are each independently selected from one to three of C₀₋₁₂alkyl,—C₂₋₁₂alkenyl, —C₂₋₁₂alkynyl, D, —CD₃, —OCD₃, halo, —CN, -oxo-, —CF₃,—OCF₃, —OCHF₂, —NO₂, —B(OH)₂, —P(O)C₀₋₃alkyl, —PO(OR¹¹)₂, —PO(OR¹¹)R¹²,C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-, C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-,aryl-C₀₋₁₂alkyl-, aryl-C₃₋₁₂cycloalkyl-, aryl-C₃₋₁₂heterocycloalkyl-,heteroaryl-C₀₋₁₂alkyl-, heteroaryl-C₃₋₁₂cycloalkyl-,heteroaryl-C₃₋₁₂heterocycloalkyl-, —C₀₋₆alkylOR¹¹, —OC(O)NR¹¹R¹²,—C(O)OR¹¹, —C(O)NR¹¹R¹², —C(O)R¹¹, —NR¹¹R¹², —NR¹¹C(O)R¹²,—NR¹³C(O)NR¹¹R¹², —S(O)_(m5)R¹¹, and —NR¹¹S(O)_(m5)R¹², any of which isoptionally substituted with independently selected Q¹ substituents.

In some embodiments of Formulas I, and Ia-Ii, G¹, G², G³, G⁴, G⁵, and G⁶are each independently selected from one to two of C₀₋₁₂alkyl,—C₂₋₁₂alkenyl, —C₂₋₁₂alkynyl, D, —CD₃, —OCD₃, halo, —CN, -oxo-, —CF₃,—OCF₃, —OCHF₂, —NO₂, —B(OH)₂, —P(O)C₀₋₃alkyl, —PO(OR¹¹)₂, —PO(OR¹¹)R¹²,—C₃₋₁₂cycloalkyl-C₀₋₁₂alkyl-, C₃₋₁₂heterocycloalkyl-C₀₋₁₂alkyl-,aryl-C₀₋₁₂alkyl-, aryl-C₃₋₁₂cycloalkyl-, aryl-C₃₋₁₂heterocycloalkyl-,heteroaryl-C₀₋₁₂alkyl-, heteroaryl-C₃₋₁₂cycloalkyl-,heteroaryl-C₃₋₁₂heterocycloalkyl-, —C₀₋₆alkylOR¹¹, —OC(O)NR¹¹R¹²,—C(O)OR¹¹, —C(O)NR¹¹R¹², —C(O)R¹¹, —NR¹¹R¹², —NR¹³C(O)R¹²,—NR¹³C(O)NR¹¹R¹², —S(O)_(m5)R¹¹, and —NR¹¹S(O)_(m5)R¹², any of which isoptionally substituted with independently selected Q¹ substituents.

In some aspects, the present invention includes a pharmaceuticalcomposition including the compound or salt of any one of the compoundsof Formula I, formulated with or without one or more pharmaceuticalcarriers.

In some aspects, the present invention includes a method for thetreatment of at least one of cancer, chronic inflammation, andautoimmune disease mediated at least in part by BTK includingadministering to a subject in need thereof a therapeutically effectiveamount of a compound or salt of the compound of Formula I.

In some aspects, the present invention includes a method of treatingcancer, chronic inflammation, or autoimmune disease in a mammalincluding administering a therapeutically effective amount of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, to themammal in need thereof.

In some aspects, the present invention includes a method of irreversiblyinhibiting tyrosine kinases, the method including administering to apatient a therapeutically effective amount of a tyrosine kinaseinhibitor including a compound of Formula I.

In some aspects, the present invention includes a method of irreversiblyinhibiting BTK, the method including administering to a patient atherapeutically effective amount of a BTK inhibitor including a compoundaccording to Formula I.

The methods described herein include administering to a subject in needa composition containing a therapeutically effective amount of one ormore BTK inhibitor compounds described herein. Without being bound bytheory, the diverse roles played by BTK signaling in varioushematopoietic cell functions, e.g., B-cell receptor activation, suggeststhat small molecule BTK inhibitors are useful for reducing the risk ofor treating a variety of diseases affected by or affecting many celltypes of the hematopoetic lineage including, e.g., autoimmune diseases,heteroimmune conditions or diseases, inflammatory diseases, cancer(e.g., B-cell proliferative disorders), and thromboembolic disorders.Further, the BTK inhibitor compounds described herein can be used toinhibit a small subset of other tyrosine kinases that share homologywith BTK by having a cysteine residue (including a Cys 481 residue) thatcan form a covalent bond with the inhibitor. Thus, a subset of tyrosinekinases other than BTK may be useful as therapeutic targets in a numberof health conditions.

The methods described herein can be used to treat an autoimmune disease,which includes, but is not limited to, rheumatoid arthritis, psoriaticarthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus,diabetes (type I and type II), myasthenia gravis, Hashimoto'sthyroiditis, Ord's thyroiditis, Graves' disease Sjögren's syndrome,multiple sclerosis, Guillain-Barré syndrome, acute disseminatedencephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome,ankylosing spondylitisis, antiphospholipid antibody syndrome, aplasticanemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome,idiopathic thrombocytopenic purpura, optic neuritis, scleroderma,primary biliary cirrhosis, Takayasu's arteritis, temporal arteritis,warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis,alopecia universalis, Behçet's disease, chronic fatigue, dysautonomia,endometriosis, interstitial cystitis, neuromyotonia, scleroderma, andvulvodynia.

The methods described herein can be used to treat heteroimmuneconditions or diseases, which include, but are not limited to graftversus host disease, transplantation, transfusion, anaphylaxis,allergies (e.g., allergies to plant pollens, latex, drugs, foods, insectpoisons, animal hair, animal dander, dust mites, or cockroach calyx),type I hypersensitivity, allergic conjunctivitis, allergic rhinitis,allergic asthma, and atopic dermatitis.

The methods described herein can be used to treat an inflammatorydisease, which includes, but is not limited to asthma, inflammatorybowel disease, appendicitis, blepharitis, bronchiolitis, bronchitis,bursitis, cervicitis, cholangitis, cholecystitis, colitis,conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis,encephalitis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis,mastitis, meningitis, myelitis myocarditis, myositis, nephritis,oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis,pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis,rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis,tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis.

The methods described herein can be used to treat a cancer, e.g., B-cellproliferative disorders, which include, but are not limited to diffuselarge B cell lymphoma, follicular lymphoma, chronic lymphocyticlymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia,lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenicmarginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodalmarginal zone B cell lymphoma, nodal marginal zone B cell lymphoma,mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma,intravascular large B cell lymphoma, primary effusion lymphoma, burkittlymphoma/leukemia, and lymphomatoid granulomatosis.

The methods described herein can be used to treat thromboembolicdisorders, which include, but are not limited to myocardial infarct,angina pectoris (including unstable angina), reocclusions or restenosesafter angioplasty or aortocoronary bypass, stroke, transitory ischemia,peripheral arterial occlusive disorders, pulmonary embolisms, and deepvenous thromboses.

Disclosed herein is a method for treating a hematological malignancy inan individual in need thereof, comprising: administering to theindividual a composition containing a therapeutic amount of at least onecompound having the structure of Formulas I, Ia-Ii or IIa-IId.

The hematological malignancy is a chronic lymphocytic leukemia (CLL),small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLLlymphoma. In some embodiments, the hematological malignancy isfollicular lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle celllymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, marginalzone lymphoma, Burkitt's lymphoma, non-Burkitt high grade B celllymphoma, or extranodal marginal zone B cell lymphoma. In someembodiments, the hematological malignancy is acute or chronicmyelogenous (or myeloid) leukemia, myelodysplastic syndrome, or acutelymphoblastic leukemia. In some embodiments, the hematologicalmalignancy is relapsed or refractory diffuse large B-cell lymphoma(DLBCL), relapsed or refractory mantle cell lymphoma, relapsed orrefractory follicular lymphoma, relapsed or refractory CLL; relapsed orrefractory SLL; relapsed or refractory multiple myeloma. In someembodiments, the hematological malignancy is a hematological malignancythat is classified as high-risk. In some embodiments, the hematologicalmalignancy is high risk CLL or high risk SLL.

B-cell lymphoproliferative disorders (BCLDs) are neoplasms of the bloodand encompass, inter alia, non-Hodgkin lymphoma, multiple myeloma, andleukemia. BCLDs can originate either in the lymphatic tissues (as in thecase of lymphoma) or in the bone marrow (as in the case of leukemia andmyeloma), and they all are involved with the uncontrolled growth oflymphocytes or white blood cells. There are many subtypes of BCLD, e.g.,chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Thedisease course and treatment of BCLD is dependent on the BCLD subtypehowever, even within each subtype the clinical presentation, morphologicappearance, and response to therapy is heterogeneous.

Malignant lymphomas are neoplastic transformations of cells that residepredominantly within lymphoid tissues. Two groups of malignant lymphomasare Hodgkin's lymphoma and non-Hodgkin's lymphoma (NHL). Both types oflymphomas infiltrate reticuloendothelial tissues. However, they differin the neoplastic cell of origin, site of disease, presence of systemicsymptoms, and response to treatment (Freedman et al., “Non-Hodgkin'sLymphomas” Chapter 134, Cancer Medicine, (an approved publication of theAmerican Cancer Society, B.C. Decker Inc., Hamilton, Ontario, 2003).

Disclosed herein is a method for treating a non-Hodgkin's lymphoma in anindividual in need thereof, comprising: administering to the individuala composition containing a therapeutic amount of at least one compoundhaving the structure of Formulas I, Ia-Ii or IIa-IId.

Further disclosed herein, is a method for treating relapsed orrefractory non-Hodgkin's lymphoma in an individual in need thereof,comprising: administering to the individual a composition containing atherapeutic amount of at least one compound having the structure ofFormulas I, Ia-Ii or IIa-IId. In some embodiments, the non-Hodgkin'slymphoma is relapsed or refractory diffuse large B-cell lymphoma(DLBCL), relapsed or refractory mantle cell lymphoma, or relapsed orrefractory follicular lymphoma.

Non-Hodgkin lymphomas (NHL) are a diverse group of malignancies that arepredominately of B-cell origin. NHL may develop in any organs associatedwith lymphatic system such as spleen, lymph nodes or tonsils and canoccur at any age. NHL is often marked by enlarged lymph nodes, fever,and weight loss. NHL is classified as either B-cell or T-cell NHL.Lymphomas related to lymphoproliferative disorders following bone marrowor stem cell transplantation are usually B-cell NHL. In the WorkingFormulation classification scheme, NHL has been divided into low-,intermediate-, and high-grade categories by virtue of their naturalhistories (see “The Non-Hodgkin's Lymphoma Pathologic ClassificationProject,” Cancer 49 (1982):2112-2135). The low-grade lymphomas areindolent, with a median survival of 5 to 10 years (Horning and Rosenberg(1984) N. Engl. J. Med. 311:1471-1475). Although chemotherapy can induceremissions in the majority of indolent lymphomas, cures are rare andmost patients eventually relapse, requiring further therapy. Theintermediate- and high-grade lymphomas are more aggressive tumors, butthey have a greater chance for cure with chemotherapy. However, asignificant proportion of these patients will relapse and requirefurther treatment.

A non-limiting list of the B-cell NHL includes Burkitt's lymphoma (e.g.,Endemic Burkitt's Lymphoma and Sporadic Burkitt's Lymphoma), CutaneousB-Cell Lymphoma, Cutaneous Marginal Zone Lymphoma (MZL), Diffuse LargeCell Lymphoma (DLBCL), Diffuse Mixed Small and Large Cell Lympoma,Diffuse Small Cleaved Cell, Diffuse Small Lymphocytic Lymphoma,Extranodal Marginal Zone B-cell lymphoma, follicular lymphoma,Follicular Small Cleaved Cell (Grade 1), Follicular Mixed Small Cleavedand Large Cell (Grade 2), Follicular Large Cell (Grade 3), IntravascularLarge B-Cell Lymphoma, Intravascular Lymphomatosis, Large CellImmunoblastic Lymphoma, Large Cell Lymphoma (LCL), LymphoblasticLymphoma, MALT Lymphoma, Mantle Cell Lymphoma (MCL), immunoblastic largecell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma,chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL),extranodal marginal zone B-cell lymphoma-mucosa-associated lymphoidtissue (MALT) lymphoma, Mediastinal Large B-Cell Lymphoma, nodalmarginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma,primary mediastinal B-cell lymphoma, lymphoplasmocytic lymphoma, hairycell leukemia, Waldenstrom's Macroglobulinemia, and primary centralnervous system (CNS) lymphoma. Additional non-Hodgkin's lymphomas arecontemplated within the scope of the present invention and apparent tothose of ordinary skill in the art.

Disclosed herein is a method for treating a DLCBL in an individual inneed thereof, comprising: administering to the individual a compositioncontaining a therapeutic amount of at least one compound having thestructure of Formulas I, Ia-Ii or IIa-IId.

As used herein, the term “Diffuse large B-cell lymphoma (DLBCL)” refersto a neoplasm of the germinal center B lymphocytes with a diffuse growthpattern and a high-intermediate proliferation index. DLBCLs representapproximately 30% of all lymphomas and may present with severalmorphological variants including the centroblastic, immunoblastic,T-cell/histiocyte rich, anaplastic and plasmoblastic subtypes. Genetictests have shown that there are different subtypes of DLBCL. Thesesubtypes seem to have different outlooks (prognoses) and responses totreatment. DLBCL can affect any age group but occurs mostly in olderpeople (the average age is mid-60s).

Disclosed herein is a method for treating diffuse large B-cell lymphoma,activated B cell-like subtype (ABC-DLBCL), in an individual in needthereof, comprising: administering to the individual an irreversible BTKinhibitor in an amount from 300 mg/day up to, and including, 1000mg/day. The ABC subtype of diffuse large B-cell lymphoma (ABC-DLBCL) isthought to arise from post germinal center B cells that are arrestedduring plasmatic differentiation. The ABC subtype of DLBCL (ABC-DLBCL)accounts for approximately 30% total DLBCL diagnoses. It is consideredthe least curable of the DLBCL molecular subtypes and, as such, patientsdiagnosed with the ABC-DLBCL typically display significantly reducedsurvival rates compared with individuals with other types of DLCBL.ABC-DLBCL is most commonly associated with chromosomal translocationsderegulating the germinal center master regulator BCL6 and withmutations inactivating the PRDM1 gene, which encodes a transcriptionalrepressor required for plasma cell differentiation.

A particularly relevant signaling pathway in the pathogenesis ofABC-DLBCL is the one mediated by the nuclear factor (NF)-κBtranscription complex. The NF-κB family comprises 5 members (p50, p52,p65, c-rel and RelB) that form homo- and heterodimers and function astranscriptional factors to mediate a variety of proliferation,apoptosis, inflammatory and immune responses and are critical for normalB-cell development and survival. NF-κB is widely used by eukaryoticcells as a regulator of genes that control cell proliferation and cellsurvival. As such, many different types of human tumors havemisregulated NF-κB: that is, NF-κB is constitutively active. ActiveNF-κB turns on the expression of genes that keep the cell proliferatingand protect the cell from conditions that would otherwise cause it todie via apoptosis.

The dependence of ABC DLBCLs on NF-κB depends on a signaling pathwayupstream of IkB kinase comprised of CARD11, BCL10 and MALT1 (the CBMcomplex). Interference with the CBM pathway extinguishes NF-κB signalingin ABC DLBCL cells and induces apoptosis. The molecular basis forconstitutive activity of the NF-κB pathway is a subject of currentinvestigation but some somatic alterations to the genome of ABC DLBCLsclearly invoke this pathway. For example, somatic mutations of thecoiled-coil domain of CARD11 in DLBCL render this signaling scaffoldprotein able to spontaneously nucleate protein-protein interaction withMALT1 and BCL10, causing IKK activity and NF-κB activation. Constitutiveactivity of the B cell receptor signaling pathway has been implicated inthe activation of NF-κB in ABC DLBCLs with wild type CARD11, and this isassociated with mutations within the cytoplasmic tails of the B cellreceptor subunits CD79A and CD79B. Oncogenic activating mutations in thesignaling adapter MYD88 activate NF-κB and synergize with B cellreceptor signaling in sustaining the survival of ABC DLBCL cells. Inaddition, inactivating mutations in a negative regulator of the NF-κBpathway, A20, occur almost exclusively in ABC DLBCL.

Indeed, genetic alterations affecting multiple components of the NF-κBsignaling pathway have been recently identified in more than 50% ofABC-DLBCL patients, where these lesions promote constitutive NF-κBactivation, thereby contributing to lymphoma growth. These includemutations of CARD11 (^(˜)10% of the cases), a lymphocyte-specificcytoplasmic scaffolding protein that—together with MALT1 and BCL10—formsthe BCR signalosome, which relays signals from antigen receptors to thedownstream mediators of NF-κB activation. An even larger fraction ofcases (^(˜)30%) carry biallelic genetic lesions inactivating thenegative NF-κB regulator A20. Further, high levels of expression ofNF-κB target genes have been observed in ABC-DLBCL tumor samples. See,e.g., U. Klein et al., (2008), Nature Reviews Immunology 8:22-23; R. E.Davis et al., (2001), Journal of Experimental Medicine 194:1861-1874; G.Lentz et al., (2008), Science 319:1676-1679; M. Compagno et al., (2009),Nature 459:712-721; and L. Srinivasan et al., (2009), Cell 139:573-586).

Disclosed herein is a method for treating a follicular lymphoma in anindividual in need thereof, comprising: administering to the individuala composition containing a therapeutic amount of at least one compoundhaving the structure of Formulas I, Ia-Ii or IIa-IId.

As used herein, the term “follicular lymphoma” refers to any of severaltypes of non-Hodgkin's lymphoma in which the lymphomatous cells areclustered into nodules or follicles. The term follicular is used becausethe cells tend to grow in a circular, or nodular, pattern in lymphnodes. The average age for people with this lymphoma is about 60.

Disclosed herein is a method for treating a CLL or SLL in an individualin need thereof, comprising: administering to the individual acomposition containing a therapeutic amount of at least one compoundhaving the structure of Formulas I, Ia-Ii or IIa-IId.

Chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL)are commonly thought as the same disease with slightly differentmanifestations. Where the cancerous cells gather determines whether itis called CLL or SLL. When the cancer cells are primarily found in thelymph nodes, lima bean shaped structures of the lymphatic system (asystem primarily of tiny vessels found in the body), it is called SLL.SLL accounts for about 5% to 10% of all lymphomas. When most of thecancer cells are in the bloodstream and the bone marrow, it is calledCLL.

Both CLL and SLL are slow-growing diseases, although CLL, which is muchmore common, tends to grow slower. CLL and SLL are treated the same way.They are usually not considered curable with standard treatments, butdepending on the stage and growth rate of the disease, most patientslive longer than 10 years. Occasionally over time, these slow-growinglymphomas may transform into a more aggressive type of lymphoma.

Chronic lymphoid leukemia (CLL) is the most common type of leukemia. Itis estimated that 100,760 people in the United States are living with orare in remission from CLL. Most (>75%) people newly diagnosed with CLLare over the age of 50. Currently CLL treatment focuses on controllingthe disease and its symptoms rather than on an outright cure. CLL istreated by chemotherapy, radiation therapy, biological therapy, or bonemarrow transplantation. Symptoms are sometimes treated surgically(splenectomy removal of enlarged spleen) or by radiation therapy(“de-bulking” swollen lymph nodes). Though CLL progresses slowly in mostcases, it is considered generally incurable. Certain CLLs are classifiedas high-risk. As used herein, “high risk CLL” means CLL characterized byat least one of the following 1) 17p13-; 2) 11q22-; 3) unmutated IgVHtogether with ZAP-70+ and/or CD38+; or 4) trisomy 12.

CLL treatment is typically administered when the patient's clinicalsymptoms or blood counts indicate that the disease has progressed to apoint where it may affect the patient's quality of life.

Small lymphocytic leukemia (SLL) is very similar to CLL described supra,and is also a cancer of B-cells. In SLL the abnormal lymphocytes mainlyaffect the lymph nodes. However, in CLL the abnormal cells mainly affectthe blood and the bone marrow. The spleen may be affected in bothconditions. SLL accounts for about 1 in 25 of all cases of non-Hodgkinlymphoma. It can occur at any time from young adulthood to old age, butis rare under the age of 50. SLL is considered an indolent lymphoma.This means that the disease progresses very slowly, and patients tend tolive many years after diagnosis. However, most patients are diagnosedwith advanced disease, and although SLL responds well to a variety ofchemotherapy drugs, it is generally considered to be incurable. Althoughsome cancers tend to occur more often in one gender or the other, casesand deaths due to SLL are evenly split between men and women. Theaverage age at the time of diagnosis is 60 years.

Although SLL is indolent, it is persistently progressive. The usualpattern of this disease is one of high response rates to radiationtherapy and/or chemotherapy, with a period of disease remission. This isfollowed months or years later by an inevitable relapse. Re-treatmentleads to a response again, but again the disease will relapse. Thismeans that although the short-term prognosis of SLL is quite good, overtime, many patients develop fatal complications of recurrent disease.Considering the age of the individuals typically diagnosed with CLL andSLL, there is a need in the art for a simple and effective treatment ofthe disease with minimum side-effects that do not impede on thepatient's quality of life. The instant invention fulfills this longstanding need in the art.

Disclosed herein is a method for treating a Mantle cell lymphoma in anindividual in need thereof, comprising: administering to the individuala composition containing a therapeutic amount of at least one compoundhaving the structure of Formulas I, Ia-Ii or IIa-IId.

As used herein, the term, “Mantle cell lymphoma” refers to a subtype ofB-cell lymphoma, due to CD5 positive antigen-naive pregerminal centerB-cell within the mantle zone that surrounds normal germinal centerfollicles. MCL cells generally over-express cyclin DI due to a t(11; 14)chromosomal translocation in the DNA. More specifically, thetranslocation is at t(11; 14)(q13; q32). Only about 5% of lymphomas areof this type. The cells are small to medium in size. Men are affectedmost often. The average age of patients is in the early 60s. Thelymphoma is usually widespread when it is diagnosed, involving lymphnodes, bone marrow, and, very often, the spleen. Mantle cell lymphoma isnot a very fast growing lymphoma, but is difficult to treat.

Disclosed herein, in certain embodiments, is a method for treating amarginal zone B-cell lymphoma in an individual in need thereof,comprising: administering to the individual a composition containing atherapeutic amount of at least one compound having the structure ofFormulas I, Ia-Ii or IIa-IId.

As used herein, the term “marginal zone B-cell lymphoma” refers to agroup of related B-cell neoplasms that involve the lymphoid tissues inthe marginal zone, the patchy area outside the follicular mantle zone.Marginal zone lymphomas account for about 5% to 10% of lymphomas. Thecells in these lymphomas look small under the microscope. There are 3main types of marginal zone lymphomas including extranodal marginal zoneB-cell lymphomas, nodal marginal zone B-cell lymphoma, and splenicmarginal zone lymphoma.

Disclosed herein, in certain embodiments, is a method for treating aMALT in an individual in need thereof, comprising: administering to theindividual a composition containing a therapeutic amount of at least onecompound having the structure of Formulas I, Ia-Ii or IIa-IId.

The term “mucosa-associated lymphoid tissue (MALT) lymphoma”, as usedherein, refers to extranodal manifestations of marginal-zone lymphomas.Most MALT lymphoma are a low grade, although a minority either manifestinitially as intermediate-grade non-Hodgkin lymphoma (NHL) or evolvefrom the low-grade form. Most of the MALT lymphoma occur in the stomach,and roughly 70% of gastric MALT lymphoma are associated withHelicobacter pylori infection. Several cytogenetic abnormalities havebeen identified, the most common being trisomy 3 or t(l 11; 18). Many ofthese other MALT lymphoma have also been linked to infections withbacteria or viruses. The average age of patients with MALT lymphoma isabout 60.

Disclosed herein, in certain embodiments, is a method for treating anodal marginal zone B-cell lymphoma in an individual in need thereof,comprising: administering to the individual a composition containing atherapeutic amount of at least one compound having the structure ofFormulas I, Ia-Ii or IIa-IId.

The term “nodal marginal zone B-cell lymphoma” refers to an indolentB-cell lymphoma that is found mostly in the lymph nodes. The disease israre and only accounts for 1% of all Non-Hodgkin's Lymphomas (NHL). Itis most commonly diagnosed in older patients, with women moresusceptible than men. The disease is classified as a marginal zonelymphoma because the mutation occurs in the marginal zone of theB-cells. Due to its confinement in the lymph nodes, this disease is alsoclassified as nodal.

Disclosed herein, in certain embodiments, is a method for treating asplenic marginal zone B-cell lymphoma in an individual in need thereof,comprising: administering to the individual a composition containing atherapeutic amount of at least one compound having the structure ofFormulas I, Ia-Ii or IIa-IId.

The term “splenic marginal zone B-cell lymphoma” refers to specificlow-grade small B-cell lymphoma that is incorporated in the World HealthOrganization classification. Characteristic features are splenomegaly,moderate lymphocytosis with villous morphology, intrasinusoidal patternof involvement of various organs, especially bone marrow, and relativeindolent course. Tumor progression with increase of blastic forms andaggressive behavior are observed in a minority of patients. Molecularand cytogenetic studies have shown heterogeneous results probablybecause of the lack of standardized diagnostic criteria.

Disclosed herein, in certain embodiments, is a method for treating aBurkitt lymphoma in an individual in need thereof, comprising:administering to the individual a composition containing a therapeuticamount of at least one compound having the structure of Formulas I,Ia-Ii or IIa-IId.

The term “Burkitt lymphoma” refers to a type of Non-Hodgkin Lymphoma(NHL) that commonly affects children. It is a highly aggressive type ofB-cell lymphoma that often starts and involves body parts other thanlymph nodes. In spite of its fast-growing nature, Burkitt's lymphoma isoften curable with modern intensive therapies. There are two broad typesof Burkitt's lymphoma—the sporadic and the endemic varieties: EndemicBurkitt's lymphoma and Sporadic Burkitt's lymphoma.

Endemic Burkitt's lymphoma involves children much more than adults, andis related to Epstein Barr Virus (EBV) infection in 95% cases. It occursprimarily in equatorial Africa, where about half of all childhoodcancers are Burkitt's lymphoma. It characteristically has a high chanceof involving the jawbone, a rather distinctive feature that is rare insporadic Burkitt's. It also commonly involves the abdomen.

Sporadic Burkitt's lymphoma is a type of Burkitt's lymphoma that affectsthe rest of the world, including Europe and the Americas. Here too, it'smainly a disease in children. The link between Epstein Barr Virus (EBV)is not as strong as with the endemic variety, though direct evidence ofEBV infection is present in one out of five patients. More than theinvolvement of lymph nodes, it is the abdomen that is notably affectedin more than 90% of the children. Bone marrow involvement is more commonthan in the sporadic variety.

Disclosed herein, in certain embodiments, is a method for treating aWaldenstrom macroglobulinemia in an individual in need thereof,comprising: administering to the individual a composition containing atherapeutic amount of at least one compound having the structure ofFormulas I, Ia-Ii or IIa-IId.

The term “Waldenstrom macroglobulinemia”, also known aslymphoplasmacytic lymphoma, is cancer involving a subtype of white bloodcells called lymphocytes. It is characterized by an uncontrolled clonalproliferation of terminally differentiated B lymphocytes. It is alsocharacterized by the lymphoma cells making an antibody calledimmunoglobulin M (IgM). The IgM antibodies circulate in the blood inlarge amounts, and cause the liquid part of the blood to thicken, likesyrup. This can lead to decreased blood flow to many organs, which cancause problems with vision (because of poor circulation in blood vesselsin the back of the eyes) and neurological problems (such as headache,dizziness, and confusion) caused by poor blood flow within the brain.Other symptoms can include feeling tired and weak, and a tendency tobleed easily. The underlying etiology is not fully understood but anumber of risk factors have been identified, including the locus 6p21.3on chromosome 6. There is a 2- to 3-fold risk increase of developing WMin people with a personal history of autoimmune diseases withautoantibodies and particularly elevated risks associated withhepatitis, human immunodeficiency virus, and rickettsiosis.

Disclosed herein, in certain embodiments, is a method for treating amyeloma in an individual in need thereof, comprising: administering tothe individual a composition containing a therapeutic amount of at leastone compound having the structure of Formulas I, Ia-Ii or IIa-IId.

Multiple myeloma, also known as MM, myeloma, plasma cell myeloma, or asKahler's disease (after Otto Kahler) is a cancer of the white bloodcells known as plasma cells. A type of B cell, plasma cells are acrucial part of the immune system responsible for the production ofantibodies in humans and other vertebrates. They are produced in thebone marrow and are transported through the lymphatic system.

Disclosed herein, in certain embodiments, is a method for treating aleukemia in an individual in need thereof, comprising: administering tothe individual a composition containing a therapeutic amount of at leastone compound having the structure of Formulas I, Ia-Ii or IIa-IId.

Leukemia is a cancer of the blood or bone marrow characterized by anabnormal increase of blood cells, usually leukocytes (white bloodcells). Leukemia is a broad term covering a spectrum of diseases. Thefirst division is between its acute and chronic forms: (i) acuteleukemia is characterized by the rapid increase of immature blood cells.This crowding makes the bone marrow unable to produce healthy bloodcells. Immediate treatment is required in acute leukemia due to therapid progression and accumulation of the malignant cells, which thenspill over into the bloodstream and spread to other organs of the body.Acute forms of leukemia are the most common forms of leukemia inchildren; (ii) chronic leukemia is distinguished by the excessive buildup of relatively mature, but still abnormal, white blood cells.Typically taking months or years to progress, the cells are produced ata much higher rate than normal cells, resulting in many abnormal whiteblood cells in the blood. Chronic leukemia mostly occurs in olderpeople, but can theoretically occur in any age group. Additionally, thediseases are subdivided according to which kind of blood cell isaffected. This split divides leukemias into lymphoblastic or lymphocyticleukemias and myeloid or myelogenous leukemias: (i) in lymphoblastic orlymphocytic leukemias, the cancerous change takes place in a type ofmarrow cell that normally goes on to form lymphocytes, which areinfection-fighting immune system cells; (ii) in myeloid or myelogenousleukemias, the cancerous change takes place in a type of marrow cellthat normally goes on to form red blood cells, some other types of whitecells, and platelets.

Within these main categories, there are several subcategories including,but not limited to, Acute lymphoblastic leukemia (ALL), Acutemyelogenous leukemia (AML), Chronic myelogenous leukemia (CML), andHairy cell leukemia (HCL).

Symptoms, diagnostic tests, and prognostic tests for each of theabove-mentioned conditions are known in the art. See, e.g., Harrison'sPrinciples of Internal Medicine®,” 16th ed., 2004, The McGraw-HillCompanies, Inc. Dey et al. (2006), Cytojournal 3(24), and the “RevisedEuropean American Lymphoma” (REAL) classification system (see, e.g., thewebsite maintained by the National Cancer Institute).

A number of animal models are useful for establishing a range oftherapeutically effective doses of BTK inhibitor compounds for treatingany of the foregoing diseases.

For example, dosing of BTK inhibitor compounds for treating anautoimmune disease can be assessed in a mouse model of rheumatoidarthritis. In this model, arthritis is induced in Balb/c mice byadministering anti-collagen antibodies and lipopolysaccharide. SeeNandakumar et al. (2003), Am. J. Pathol 163:1827-1837.

In another example, dosing of BTK inhibitors for the treatment of B-cellproliferative disorders can be examined in, e.g., a human-to-mousexenograft model in which human B-cell lymphoma cells (e.g. Ramos cells)are implanted into immunodefficient mice (e.g., “nude” mice) asdescribed in, e.g., Pagel et al. (2005), Clin Cancer Res11(13):4857-4866.

Animal models for treatment of thromboembolic disorders are also known.

The therapeutic efficacy of the compound for one of the foregoingdiseases can be optimized during a course of treatment. For example, asubject being treated can undergo a diagnostic evaluation to correlatethe relief of disease symptoms or pathologies to inhibition of in vivoBTK activity achieved by administering a given dose of a BTK inhibitor.Cellular assays known in the art can be used to determine in vivoactivity of BTK in the presence or absence of an BTK inhibitor. Forexample, since activated BTK is phosphorylated at tyrosine 223 (Y223)and tyrosine 551 (Y551), phospho-specific immunocytochemical staining ofP—Y223 or P-Y551-positive cells can be used to detect or quantifyactivation of BTK in a population of cells (e.g., by FACS analysis ofstained vs unstained cells). See, e.g., Nisitani et al. (1999), Proc.Natl. Acad. Sci, USA 96:2221-2226. Thus, the amount of the BTK inhibitorcompound that is administered to a subject can be increased or decreasedas needed so as to maintain a level of BTK inhibition optimal fortreating the subject's disease state.

Compounds disclosed herein irreversibly inhibit BTK and may be used totreat mammals suffering from Bruton's tyrosine kinase-dependent orBruton's tyrosine kinase mediated conditions or diseases, including, butnot limited to, cancer, autoimmune and other inflammatory diseases.Compounds disclosed herein have shown efficacy in a wide variety ofdiseases and conditions that are described herein.

A further aspect resides in the use of compounds of Formulas I, Ia-Ii orIIa-IId or a pharmaceutically acceptable salt thereof for themanufacture of a medicament to be used for the treatment of chronic Bcell disorders in which T cells play a prominent role.

In yet another aspect, the compounds of Formulas I, Ia-Ii or IIa-IId areused for the manufacture of a medicament to be used for the treatment ofBTK-mediated diseases or conditions. These include, but are not limitedto, the treatment of B cell lymphomas resulting from chronic active Bcell receptor signaling.

BTK mediated disorders or BTK mediated conditions as used herein, meanany disease state or other deleterious condition in which B cells, mastcells, myeloid cells or osteoclasts play a central role. These diseasesinclude but are not limited to, immune, autoimmune and inflammatorydiseases, allergies, infectious diseases, bone resorption disorders andproliferative diseases.

Immune, autoimmune and inflammatory diseases that can be treated orprevented with the compounds of Formulas I, Ia-Ii or IIa-IId furtherinclude rheumatic diseases (e.g. infectious arthritis, progressivechronic arthritis, deforming arthritis, traumatic arthritis, goutyarthritis, osteoporosis, Reiter's syndrome, polychondritis, acutesynovitis and spondylitis), glomerulonephritis (with or withoutnephrotic syndrome), autoimmune hematologic disorders (e.g. hemolyticanemia, aplasic anemia, idiopathic thrombocytopenia, and neutropenia),and autoimmune inflammatory bowel diseases (e.g. ulcerative colitis andCrohn's disease), host versus graft disease, allograft rejection,chronic thyroiditis, schleroderma, primary billiary cirrhosis, systemiclupus erythematosis, contact dermatitis, eczema, skin sunburns, chronicrenal insufficiency, Stevens-Johnson syndrome, inflammatory pain,idiopathic sprue, cachexia, sarcoidosis, kerato conjunctivitis, otitismedia, periodontal disease, pulmonary interstitial fibrosis,pneumoconiosis, pulmonary insufficiency syndrome, pulmonary emphysema,pulmonary fibrosis, silicosis, chronic inflammatory pulmonary disease(e.g. chronic obstructive pulmonary disease) and other inflammatory orobstructive disease on airways.

Allergies that can be treated or prevented include, among others,allergies to foods, food additives, insect poisons, dust mites, pollen,animal materials and contact allergans, type I hypersensitivity allergicasthma, allergic conjunctivitis.

Infectious diseases that can be treated or prevented include, amongothers, sepsis, septic shock, endotoxic shock, sepsis by Gram-negativebacteria, shigellosis, meningitis, cerebral malaria, pneumonia,tuberculosis, viral myocarditis, viral hepatitis (hepatitis A, hepatitisB and hepatitis C), HIV infection, retinitis caused by cytomegalovirus,influenza, herpes, treatment of infections associated with severe burns,myalgias caused by infections, cachexia secondary to infections, andveterinary viral infections such as lentivirus, caprine arthritic virus,visna-maedi virus, feline immunodeficiency virus, bovineimmunodeficiency virus or canine immunodeficiency virus.

In some embodiments of Formula I, compounds are present as a material insubstantially pure form.

In some embodiments of Formula I, compounds are selected from any one ofthe Examples herein or a pharmaceutically acceptable salt thereof.

Each variable definition above includes any subset thereof and thecompounds of Formula I include any combination of such variables orvariable subsets.

The present invention includes the compounds and salts thereof, theirphysical forms, preparation of the compounds, useful intermediates, andpharmaceutical compositions and formulations thereof.

The compounds of the present invention and the term “compound” in theclaims include any pharmaceutically acceptable salts or solvates, andany amorphous or crystal forms, or tautomers, whether or notspecifically recited in context.

The present invention includes all isomers of the compounds. Compoundsmay have one or more asymmetric carbon atoms and can exist as two ormore stereoisomers. Where a compound of the invention contains analkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers arepossible. Where the compound contains, for example, a keto or oximegroup or an aromatic moiety, tautomeric isomerism (‘tautomerism’) canoccur. A single compound may exhibit more than one type of isomerism.

The present invention includes any stereoisomers, even if notspecifically shown, individually as well as mixtures, geometric isomers,and pharmaceutically acceptable salts thereof, including compoundsexhibiting more than one type of isomerism. Where a compound orstereocenter is described or shown without definitive stereochemistry,it is to be taken to embrace all possible individual isomers,configurations, and mixtures thereof. Thus, a material sample containinga mixture of stereoisomers would be embraced by a recitation of eitherof the stereoisomers or a recitation without definitive stereochemistry.Also contemplated are any cis/trans isomers or tautomers of thecompounds described. When a tautomer of the compound of Formula Iexists, the compound of Formula I of the present invention includes anypossible tautomers and pharmaceutically acceptable salts thereof, andmixtures thereof, except where specifically stated otherwise.

DETAILED DESCRIPTION OF THE INVENTION

Described herein are compounds of Formula I, which include compounds ofFormulas Ia-Ii and IIa-IId, and compositions and formulations containingsuch compounds, and methods of using and making such compounds. Thesecompounds are useful in treating diseases or conditions modulated atleast in part by BTK.

In an embodiment, a compound according to Formula I and aboveembodiments is provided, wherein the compound of Formula I isrepresented by the compound of Formula IIa:

wherein, R¹-R⁴, G², G³, L¹, L², X, Y, and Z¹-Z⁴, are as previouslydescribed for a compound of Formula I and B¹ and B² are independentlyselected from C₆cycloalkyl, C₆heterocycloalkyl, C₆aryl, or C₆heteroaryl.

In an embodiment, a compound according to Formula I and aboveembodiments is provided, wherein the compound of Formula I isrepresented by the compound of Formula IIb:

wherein, R¹-R⁴, B¹, B², L¹, L², Y, and Z¹-Z⁴, are as previouslydescribed for a compound of Formula I, Z⁵ and Z⁶ are each independentlyselected from C(R^(a)) or N, where R^(a) is alkyl or H, and n and m areeach independently selected from 0, 1, or 2.

In an embodiment, a compound according to Formula I and aboveembodiments is provided, wherein the compound of Formula I isrepresented by the compound of Formula IIc:

wherein, R¹-R⁴, B¹, B², L¹, L², and Z¹-Z⁴, are as previously describedfor a compound of Formula I, Z⁵ and Z⁶ are each independently selectedfrom C or N, and n and m are each independently selected from 0, 1, or2.

In an embodiment, a compound according to Formula I and aboveembodiments is provided, wherein the compound of Formula I isrepresented by the compound of Formula IId:

wherein, R¹-R⁴, L¹, L², G², G³, and Z¹-Z⁴, are as previously describedfor a compound of Formula I, Z⁵ and Z⁶ are each independently selectedfrom C or N, B¹ and B² are independently selected from C₆cycloalkyl,C₆heterocycloalkyl, C₆aryl, or C₆heteroaryl, and n and m are eachindependently selected from 0, 1, or 2.

The present invention includes the compounds, intermediates, examplesand synthetic methods described herein. Compounds of Formula I areprepared according to reaction schemes described herein. Unlessotherwise indicated, the substituents in the schemes are defined asabove.

Synthetic Methods:

Compounds of the present invention include the intermediates, examples,and synthetic methods described herein. Synthetic methods providedherein are generally preceded by their respective synthetic schemes.Where a procedure for an intermediate or example refers to an analogousprocedure for an analogous intermediate or example, such referenceincludes the procedure for that analogous intermediate or example, theassociated synthetic scheme as well as the procedures and schemesutilized for the synthesis of the analogous intermediate or example.

The compounds of Formulas I, Ia-Ii and IIa-d may be prepared by themethods described below, together with synthetic methods known in theart of organic chemistry, or modifications and derivatizations that arefamiliar to those of ordinary skill in the art. The starting materialsused herein are commercially available or may be prepared by routinemethods known in the art [such as those methods disclosed in standardreference books such as the Compendium of Organic Synthetic Methods,Vol. I-VI (Wiley-Interscience); or the Comprehensive OrganicTransformations, by R. C. Larock (Wiley-Interscience)]. Preferredmethods include, but are not limited to, those described below.

During any of the following synthetic sequences it may be necessaryand/or desirable to protect sensitive or reactive groups on any of themolecules concerned. This can be achieved by means of conventionalprotecting groups, such as those described in T. W. Greene, ProtectiveGroups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Greene andP. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley &Sons, 1991, and T. W. Greene and P. G. M. Wuts, Protective Groups inOrganic Chemistry, John Wiley & Sons, 1999, which are herebyincorporated by reference.

Compounds of Formulas I, Ia-Ii and IIa-d, or their pharmaceuticallyacceptable salts, can be prepared according to the reaction schemesdiscussed hereinbelow and utilizing ordinary skill in the art. Unlessotherwise indicated, the substituents in the schemes are defined asabove. Isolation and purification of the products is accomplished bystandard procedures, which are known to a chemist of ordinary skill.

When a general or exemplary synthetic procedure is referred to, oneskilled in the art can readily determine the appropriate reagents, ifnot indicated, extrapolating from the general or exemplary procedures.Some of the general procedures are given as examples for generalpreparation of compounds. One skilled in the art can readily adapt suchprocedures to the synthesis of other specific compounds. Representationof an unsubstituted position in structures shown or referred to in thegeneral procedures is for convenience and does not preclude substitutionas described elsewhere herein. For specific groups that can be present,either as groups in the general procedures or as optional substituentsnot shown, refer to the descriptions in the remainder of this document,including the claims and detailed description.

A general procedure for the synthesis of compounds of Formulas I, Ia-Iiand IIa-d is shown in the General Scheme, below.

Where A, B¹, B², L¹, X, R², R³, and R⁴ are as defined previously for acompound of Formulas I, Ia-Ii and IIa-d and LG is equal to a suitableleaving group such as triflate, mesylate, tosylate, HATU, Cl, Br or I.

In a typical preparation of a compound of Formulas I, Ia-Ii and IIa-d, acompound of Formula (a) was reacted under Suzuki coupling conditionswith a suitable boronic acid. Suitable conditions include, but are notlimited to, treating compounds of Formula (a) with a suitable base, suchas Cs₂CO₃ or K₂CO₃, and a suitable palladium catalyst, such asPd(dppf)Cl₂. DCM. Suitable solvents for use in the above synthesisinclude 1,4-dioxane, water, DME and mixtures thereof. The mixture wasdegassed with nitrogen six times and refluxed for about 16 h undernitrogen atmosphere to afford the compound of Formula (b). The aboveprocess was carried out at temperatures between about 50° C. and about150° C. Preferably, the reaction was carried out at about 100° C. Theabove process was preferably carried out at or about atmosphericpressure although higher or lower pressures may be used if desired.Substantially equimolar amounts of reactants were preferably usedalthough higher or lower amounts may be used if desired.

The compound of Formula (b) was reacted with a suitable boronic acidunder Suzuki coupling conditions. Suitable conditions include, but arenot limited to, treating compounds of Formula (b) with a suitable base,such as Cs₂CO₃ or K₂CO₃, and a suitable palladium catalyst, such asPd(dppf)Cl₂.DCM or Pd(PPh₃)₄. Suitable solvents for use in the abovesynthesis include 1,4-dioxane, water, DME and mixtures thereof. Themixture was degassed with nitrogen six times and refluxed for about 5 hunder nitrogen atmosphere to afford the compound of Formula (c). Theabove process was carried out at temperatures between about 40° C. andabout 120° C. Preferably, the reaction was carried out at about 90° C.The above process was preferably carried out at or about atmosphericpressure although higher or lower pressures may be used if desired.Substantially equimolar amounts of reactants were preferably usedalthough higher or lower amounts may be used if desired.

The compound of Formula (c) was reacted under hydrogen atmosphere withpalladium on carbon, preferably degassing the mixture with hydrogenabout 6 times. Suitable solvents for use in the above synthesis includeethyl acetate and methanol. The above process was carried out attemperatures between about 10° C. and about 60° C., or preferably atambient temperature, to afford the compound of Formula (d). The aboveprocess was preferably carried out at or about atmospheric pressurealthough higher or lower pressures may be used if desired. Substantiallyequimolar amounts of reactants were preferably used although higher orlower amounts may be used if desired.

The compound of Formula (d) was reacted with a suitable acryloylchloride with a suitable base. Suitable bases include organic bases suchas TEA or DIPEA. The above process was carried out at temperaturesbetween about −10° C. and about ambient temperature, or preferably at 0°C., to afford the compound of Formula (d). The above process waspreferably carried out at or about atmospheric pressure although higheror lower pressures may be used if desired. Substantially equimolaramounts of reactants were preferably used although higher or loweramounts may be used if desired.

EXAMPLES: PREPARATIONS AND INTERMEDIATES

2-chloro-6-(3-nitrophenyl)nicotinonitrile (3)

To a solution of 3-nitrophenylboronic acid 2 (5.19 g, 30 mmol), Cs₂CO₃(19.56 g, 60 mmol) and 2,6-dichloronicotinonitrile 1 (5.51 g, 33 mmol)in dry 1,4-dioxane (100 mL) was added Pd(dppf)Cl₂.DCM (2.4 g, 3.0 mmol)under nitrogen atmosphere, and the mixture was degassed with nitrogen 6times, then refluxed for 16 h under nitrogen atmosphere. After coolingto room temperature, the solvent was evaporated and the residue waspurified by flash chromatography, eluting with 20:1 to 3:1 PE/EA toafford the title compound as a yellow solid (1.6 g, 21%).

2-chloro-6-(3-nitrophenyl)nicotinamide (4)

To a solution of 2-chloro-6-(3-nitrophenyl)nicotinonitrile 3 (259 mg,1.0 mmol) and acetaldoxime (88 mg, 1.5 mmol) in tetrahydrofuran (5 mL)and water (5 mL) was added CuCl₂ (15 mg, 0.1 mmol) under nitrogenatmosphere, and the mixture was degassed with nitrogen 6 times, thenheated to 90° C. and stirred for 16 h under nitrogen atmosphere. Aftercooling to room temperature, the solvent was evaporated and the crudeproduct was purified by flash chromatography, eluting with 20:1 DCM/MeOHto afford the title compound as a yellow solid (240 mg, 84%). MS (ESI):m/z=277.9 [M+H]+.

6-(3-nitrophenyl)-2-(4-phenoxyphenyl)nicotinamide (6)

To a solution of 2-chloro-6-(3-nitrophenyl)nicotinamide 4 (240 mg, 0.87mmol), Cs₂CO₃ (567 mg, 1.74 mmol) and biphenyl-4-ylboronic acid 5 (203mg, 0.95 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) was addedPd₂(dba)₃ (80 mg, 0.09 mmol) under nitrogen atmosphere, and the mixturewas degassed with nitrogen 6 times, then refluxed for 16 h undernitrogen atmosphere. After cooling to room temperature, the solvent wasevaporated and the crude product was purified by flash chromatographyeluting with 150:1 DCM/MeOH to afford the title compound as a yellowsolid (110 mg, crude).

6-(3-aminophenyl)-2-(4-phenoxyphenyl)nicotinamide (7)

To a solution of 6-(3-nitrophenyl)-2-(4-phenoxyphenyl)nicotinamide 6(110 mg, 0.27 mmol) in ethyl acetate (5 mL) was added Pd/C (10 mg) underhydrogen atmosphere, and the mixture was degassed with hydrogen 6 times,then stirred for 16 h at ambient temperature under hydrogen atmosphere.The solution was filtered and the filtrate was evaporated to the crudeproduct as red oil (61 mg, 60%). MS (ESI): m/z=382.1 [M+H]⁺.

Example 1 6-(3-acrylamidophenyl)-2-(4-phenoxyphenyl)nicotinamide

To a solution of 6-(3-aminophenyl)-2-(4-phenoxyphenyl)nicotinamide 7 (38mg, 0.1 mmol) in DCM (5 mL) was added TEA (0.05 mL, 0.4 mmol) andacryloyl chloride 8 (9 mg, 0.1 mmol) at 0° C. The mixture was stirred at0° C. for 10 minutes. The solvent was removed and the residue waspurified by Prep-TLC eluting with 25:1 DCM/MeOH to afford the titlecompound (30 mg, 71%) as white solid. ¹H NMR (400 MHz, DMSO) δ 10.36 (s,1H), 8.43 (s, 1H), 7.72-7.97 (m, 7H), 7.49 (s, 1H), 7.33-7.52 (m, 3H),7.24 (t, J=6.9 Hz, 1H), 6.9-7.13 (m, 4H), 6.45 (dd, J=16.9, 10.0 Hz,1H), 6.30 (d, J=16.9 Hz, 1H), 5.79 (d, J=10.5 Hz, 1H), MS (ESI, methodA): m/z=436.0 [M+H]⁺, t_(R)=1.553 min., HPLC: 97.5% (214 nm), 98.0% (254nm).

2,6-dichloronicotinamide (2)

To 2,6-dichloronicotinonitrile 1 (1.73 g, 10 mmol) was added conc H₂SO₄(10 mL) and water (2 mL). The mixture was heated to 90° C. and stirredfor 1 h. After cooling to room temperature, the solution was poured intoice-cold water, then adjusted to PH=8 with ammonia water. Theprecipitate was filtered, washed with water (20 mL) and dried undervacuum to afford the title compound as an brown solid (1.4 g, 73%). MS(ESI): m/z=191.1 [M+H]+.

6-chloro-2-(4-phenoxyphenyl)nicotinamide (4)

To a solution of 2,6-dichloronicotinamide 2 (668 mg, 3.5 mmol), Cs₂CO₃(1.14 g, 7 mmol) and 4-phenoxyphenylboronic acid 3 (749 mg, 3.5 mmol) in1,4-dioxane (30 mL) was added Pd(dppf)Cl₂-DCM (285 mg, 0.35 mmol) undernitrogen atmosphere, and the mixture was degassed with nitrogen 6 times,then refluxed for 16 h under nitrogen atmosphere. After cooling to roomtemperature, the solvent was evaporated and the residue was purified byflash chromatography, eluting with 20:1 to 3:1 petroleum ether/ethylacetate (PE/EA) to afford the title compound as a yellow solid (611 mg,53%). MS (ESI): m/z=325.0 [M+H]⁺.

tert-butyl-4-(5-carbamoyl-6-(4-phenoxyphenyl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(6)

To a solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine5 (232 mg, 0.75 mmol), K₂CO₃ (207 mg, 1.50 mmol) and6-chloro-2-(4-phenoxyphenyl)nicotinamide 4 (162 mg, 0.50 mmol) in1,2-dimethoxyethane (5 mL) and water (1 mL) was added Pd(PPh₃)₄(115 mg,0.10 mmol) under nitrogen atmosphere, and the mixture was degassed withnitrogen 6 times, then heated to 90° C. and stirred for 5 h undernitrogen atmosphere. After cooling to room temperature, the solvent wasevaporated and the crude product was purified by flash chromatography,eluting with 70:1 DCM/MeOH to afford the title compound as a white solid(232 mg, crude).

tert-butyl4-(5-carbamoyl-6-(4-phenoxyphenyl)pyridin-2-yl)piperidine-carboxylate(7)

To a solution of4-(5-carbamoyl-6-(4-phenoxyphenyl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate6 (232 mg, 0.75 mmol) in ethyl acetate (5 mL) was added Pd/C (10 mg)under hydrogen atmosphere, and the mixture was degassed with hydrogen 6times, then stirred for 16 h at ambient temperature under hydrogenatmosphere. The solution was filtered and the filtrate was evaporated tothe crude product as brown solid (215 mg, 60% for two steps). MS (ESI):m/z=474.1 [M+H]⁺.

2-(4-phenoxyphenyl)-6-(piperidin-4-yl)nicotinamide (Example 2) (8)

To a solution of tert-butyl4-(5-carbamoyl-6-(4-phenoxyphenyl)pyridin-2-yl)piperidine-1-carboxylate7 (215 mg, 0.45 mmol) in dry dichloromethane (6 mL) was added TFA (2mL), and the resulting mixture was stirred for 1 h at ambienttemperature. The solvent was removed and the residue was partitionedbetween saturated aqueous sodium bicarbonate (30 mL) and ethyl acetate(20 mL). The organic phase was separated, dried over anhydrous sodiumsulfate, filtered and concentrated. The crude residue was purified byflash chromatography, eluting with 5:1 DCM/MeOH to afford the titlecompound as a white solid (120 mg, 71%). MS (ESI): m/z=374.2 [M+H]+.

Example 3 6-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide

To a solution of 2-(4-phenoxyphenyl)-6-(piperidin-4-yl)nicotinamide 8(26 mg, 0.07 mmol) in DCM (5 mL) was added TEA (0.05 mL, 0.4 mmol) andacryloyl chloride 9 (7 mg, 0.07 mmol) at 0° C. The mixture was stirredat 0° C. for 10 minutes. The solvent was removed and the residue waspurified by Prep-TLC eluting with 25:1 DCM/MeOH to afford the titlecompound (13 mg, 44%) as white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.90 (d,J=8.0 Hz, 1H), 7.71-7.62 (m, 2H), 7.42-7.31 (m, 2H), 7.21-7.11 (m, 2H),7.10-7.01 (m, 4H), 6.60 (dd, J=16.8, 10.5 Hz, 1H), 6.26 (dd, J=16.8, 2.0Hz, 1H), 5.84 (s, 1H), 5.68 (dd, J=10.5, 2.0 Hz, 1H), 5.54 (s, 1H), 4.79(d, J=13.3 Hz, 1H), 4.13 (d, J=12.8 Hz, 1H), 3.17 (t, J=12.3 Hz, 1H),3.39 (t, J=11.7 Hz, 1H), 2.76 (t, J=11.7 Hz, 1H), 2.03 (br, 2H), 1.80(ddd, J=25.5, 12.5, 4.2 Hz, 2H). MS (ESI, method A): m/z=428.0 [M+H]⁺,t_(R)=1.480 min. HPLC: 96.7% (214 nm), 99.3% (254 nm).

tert-butyl 4-(6-chloro-5-cyanopyridin-2-yl)piperazine-1-carboxylate (3)

To a solution of 2,6-dichloronicotinonitrile 1 (519 mg, 3.0 mmol) andtert-butyl piperazine-1-carboxylate 2 (558 mg, 3.0 mmol) in ethanol (15mL) was added K₂CO₃ (636 mg, 6.0 mmol), and the resulting solution wasrefluxed for 4 h. After cooling to room temperature, the solvent wasevaporated and the crude product was purified by flash chromatography,eluting with 5:1 to 2:1 PE/EA to afford the title compound as a whitesolid (600 mg, 62%). MS (ESI): m/z=345.1 [M+Na]⁺.

6-chloro-2-(4-phenoxyphenyl)nicotinamide (4)

To tert-butyl-(6-chloro-5-cyanopyridin-2-yl)piper azine-1-carboxylate3(600 mg, 10 mmol) was added H₂SO₄ (conc., 5 mL) and water (1 mL). Themixture was heated to 90° C. and stirred for 1 h. After cooling to roomtemperature, the solution was poured into ice-cold water, then adjustedto PH=8 with ammonia water. The precipitate was filtered, washed withwater (20 mL) and dried under vacuum to afford the title compound as anoff-white solid (420 mg, 94%). MS (ESI): m/z=241.0 [M+H]⁺.

2-(4-phenoxyphenyl)-6-(piperazin-1-yl)nicotinamide (Example 4) (6)

To a solution of 6-chloro-2-(4-phenoxyphenyl)nicotinamide 4 (420 mg,1.75 mmol), K₂CO₃ (483 mg, 3.5 mmol) and 4-phenoxyphenylboronic acid 5(374 mg, 1.75 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was addedPd(PPh₃)₄(231 mg, 0.20 mmol) under nitrogen atmosphere, and the mixturewas degassed with nitrogen 6 times, then heated to 90° C. and stirredfor 5 h under nitrogen atmosphere. After cooling to room temperature,the solvent was evaporated and the crude product was purified by flashchromatography eluting with 70:1 DCM/MeOH to afford the title compoundas a white solid (260 mg, 58%). MS (ESI): m/z=375.0 [M+H]⁺.

Example 5 6-(4-acryloylpiperazin-1-yl)-2-(4-phenoxyphenyl)nicotinamide

To a solution of 2-(4-phenoxyphenyl)-6-(piperazin-1-yl)nicotinamide 6(59 mg, 0.16 mmol) in DCM (5 mL) was added TEA (0.05 mL, 0.4 mmol) andacryloyl chloride 7 (14 mg, 0.16 mmol) at 0° C. The mixture was stirredat 0° C. for 10 minutes. The solvent was removed and the residue waspurified by Prep-TLC eluting with 25:1 DCM/MeOH to afford the titlecompound (27 mg, 40%) as light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ8.04 (d, J=8.7 Hz, 1H), 7.64 (d, J=8.2 Hz, 2H), 7.40 (t, J=7.6 Hz, 2H),7.18 (t, J=7.3 Hz, 1H), 7.08 (dd, J=12.0, 8.4 Hz, 4H), 6.66 (d, J=8.5Hz, 1H), 6.64-6.56 (m, 1H), 6.37 (d, J=16.7 Hz, 1H), 5.77 (d, J=10.6 Hz,1H), 5.57 (s, 1H), 5.33 (s, 1H), 3.81 (s, 4H), 3.73 (s, 4H). MS (ESI,method A): m/z=429.2 [M+H]⁺, t_(R)=1.454 min., HPLC: 97.5% (214 nm),98.0% (254 nm).

6-chloro-2-(4-phenoxyphenyl)nicotinamide (1)

6-chloro-2-(4-phenoxyphenyl)nicotinamide 1 was synthesized by using thesame procedure above providing a yellow solid (611 mg, 53%). MS (ESI):m/z=325.0 [M+H]⁺.

tert-butyl-3-(5-carbamoyl-6-(4-phenoxyphenyl)pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate(3)

The title compound was synthesized using a procedure analogous to theprocedure described in tert-butyl4-(5-carbamoyl-6-(4-phenoxyphenyl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylateprovided as white solid (300 mg, crude). MS (ESI): m % z=458.2 [M+H]⁺.

tert-butyl-3-(5-carbamoyl-6-(4-phenoxyphenyl)pyridin-2-yl)pyrrolidine-1-carboxylate(4)

The title compound was synthesized using a procedure analogous to theprocedure described in tert-butyl4-(5-carbamoyl-6-(4-phenoxyphenyl)pyridin-2-yl)piperidine-1-carboxylateprovided as white solid (240 mg, 45% for two steps). MS (ESI): m, =460.1[M+H]⁺.

2-(4-phenoxyphenyl)-6-(pyrrolidin-3-yl)nicotinamide (5)

The title compound was synthesized using a procedure analogous to theprocedure described in2-(4-phenoxyphenyl)-6-(piperidin-4-yl)nicotinamide as white solid (190mg, crude). MS (ESI): m/z=360.1 [M+H]⁺.

Example 6 6-(1-acryloylpyrrolidin-3-yl)-2-(4-phenoxyphenyl)nicotinamide

The title compound was synthesized using a procedure analogous to theprocedure described in Example 3 as a white solid (18 mg, 29%). ¹H NMR(300 MHz, CD₃OD) δ 7.85 (d, J=7.9 Hz, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.37(m, 3H), 7.15 (t, J=7.4 Hz, 1H), 7.02 (m, 4H), 6.65 (dd, J=16.7, 10.6Hz, 1H), 6.28 (m, 1H), 5.74 (dd, J=9.5, 7.4 Hz, 1H), 3.98 (m, 2H), 3.69(m, 3H), 2.34 (dtd, J=30.9, 12.6, 8.0 Hz, 2H). MS (ESI, method A):m/z=414.2 [M+H]¹, t_(R)=1.421 min. HPLC: 100% (214 nm), 100% (254 nm).

tert-butyl 4-(6-chloro-5-cyanopyridin-2-yl)piperazine-1-carboxylate (3)

To a solution of 6-chloro-2-(4-phenoxyphenyl)nicotinamide 1 (130 mg, 0.4mmol) and 4-nitrophenylboronic acid 2 (67 mg, 0.4 mmol) in DME (10mL)/water (3 mL), was added K₂CO₃ (110 mg, 0.8 mmol) and Pd(dppf)Cl₂ (33mg, 0.04 mmol) under nitrogen atmosphere, and the mixture was degassedwith nitrogen 6 times, then heated to 90° C. and stirred for 5 h undernitrogen atmosphere. After cooling to room temperature, the solvent wasevaporated and the crude product was purified by flash chromatographyeluting with 70:1 DCM/MeOH to afford the title compound as a white solid(60 mg, crude). MS (ESI): m/z=412.1 [M+H]⁺.

6-(4-aminophenyl)-2-(4-phenoxyphenyl)nicotinamide (4)

To a solution of tert-butyl4-(6-chloro-5-cyanopyridin-2-yl)piperazine-1-carboxylate 3 (60 mg, 0.15mmol) in ethyl acetate (5 mL) was added Pd/C (6 mg) under hydrogenatmosphere, and the mixture was degassed with hydrogen 6 times, thenstirred for 16 h at ambient temperature under hydrogen atmosphere. Thesolution was filtered and the filtrate was evaporated to the crudeproduct as brown solid (42 mg, 90%). MS (ESI): m/z=382.0 [M+H]⁺.

Example 7 6-(4-acrylamidophenyl)-2-(4-phenoxyphenyl)nicotinamide

To a solution of 6-(4-aminophenyl)-2-(4-phenoxyphenyl)nicotinamide 4 (42mg, 0.11 mmol) in DCM (5 mL) was added TEA (0.05 mL, 0.4 mmol) andacryloyl chloride 5 (10 mg, 0.11 mmol) at 0° C. The mixture was stirredat 0° C. for 10 minutes. The solvent was removed and the residue waspurified by Prep-TLC eluting with 25:1 DCM/MeOH to afford the titlecompound (2.5 mg, 10%) as white solid. ¹H NMR (300 MHz, CD₃OD) δ8.17-8.11 (m, 1H), 7.98-7.92 (m, 1H), 7.90-7.84 (m, 1H), 7.81 (s, 3H),7.69-7.60 (m, 2H), 7.58-7.52 (m, 1H), 7.42-7.34 (m, 2H), 7.18-7.12 (m,1H), 7.10-7.00 (m, 3H), 6.47-6.38 (m, 2H), 5.82-5.76 (m, 1H). MS (ESI,method A): m % z=435.9 [M+H]⁺, t_(R)=1.540 min., HPLC: 97.5% (214 nm),98.7% (254 nm).

tert-butyl5-(trifluoromethylsulfonyloxy)-3,4-dihydropyridine-1(2H)-carboxylate (3)

To a solution of tert-butyl 3-oxopiperidine-1-carboxylate 1 (495 mg, 5.0mmol) in tetrahydrofuran (10 mL) in a three-necked flask was addedlithium diisopropylamide (2.0M, 2.5 mL, 5.0 mmol) at −78° C. Afterstirring for 2 h at −78° C., a solution oftrifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide 2 (1.8g, 5.0 mmol) in tetrahydrofuran (5 mL) was added, and the solution wasstirred for another 30 min at this temperature, then warmed to roomtemperature and stirred for 3 h. Water (30 mL) was added to quench thereaction, and the solution was extracted with ethyl acetate (3×30 mL).The organic layers were combined, dried over anhydrous sodium sulfate,filtered and concentrated. The residue was purified by silica gel columnchromatography eluting with petroleum ether to afford the title compoundas brown oil (1.4 g, 85%).

tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1(2H)carboxylate (5)

To a solution of4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) 4 (559 mg,2.2 mmol), KOAc (588 mg, 6.0 mmol) and tert-butyl5-(trifluoromethylsulfonyloxy)-3,4-dihydropyridine-1(2H)-carboxylate 3(662 mg, 2.0 mmol) in dry 1,4-dioxane (10 mL) was added Pd(dppf)Cl₂.DCM(326 mg, 0.4 mmol) under nitrogen atmosphere, and the mixture wasdegassed with nitrogen 6 times, then heated to 85° C. and stirredovernight under nitrogen atmosphere. After cooling to room temperature,the solvent was evaporated and the crude product was purified by silicagel column chromatography, eluting with 100:1 to 20:1 PE/EA to affordthe title compound as brown oil (336 mg, 54%).

tert-butyl-5-(5-carbamoyl-6-(4-phenoxyphenyl)pyridin-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate(7)

To a solution of tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate5 (260 mg, 0.84 mmol), Cs₂CO₃ (456 mg, 1.4 mmol) and6-chloro-2-(4-phenoxyphenyl)nicotinamide 6 (227 mg, 0.7 mmol) in1,4-dioxane (10 mL) was added Pd(dppf)Cl₂.DCM (57 mg, 0.07 mmol) undernitrogen atmosphere, and the mixture was degassed with nitrogen 6 times,then heated to 90° C. and stirred overnight under nitrogen atmosphere.After cooling to room temperature, the solvent was evaporated and thecrude product was purified by silica gel column chromatography elutingwith 100:1 to 20:1 DCM/MeOH to afford the title compound as white solid(240 mg, 71%). MS (ESI): m/z=472.2 [M+H]⁺.

tert-butyl3-(5-carbamoyl-6-(4-phenoxyphenyl)pyridin-2-yl)piperidine-1-carboxylate(8)

To a solution of tert-butyl5-(5-carbamoyl-6-(4-phenoxyphenyl)pyridin-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate7 (240 mg, 0.5 mmol) in ethyl acetate (5 mL) was added Pd/C (24 mg)under hydrogen atmosphere, and the mixture was degassed with hydrogen 6times, then stirred for 16 h at ambient temperature under hydrogenatmosphere. The solution was filtered and the filtrate was evaporated tothe crude product as brown solid (230 mg, crude). MS (ESI): m/z=474.2[M+H]⁺.

2-(4-phenoxyphenyl)-6-(piperidin-3-yl)nicotinamide (9)

To a solution of tert-butyl3-(5-carbamoyl-6-(4-phenoxyphenyl)pyridin-2-yl)piperidine-1-carboxylate8 (150 mg, 0.32 mmol) in dry dichloromethane (6 mL) was added TFA (2mL), and the resulting mixture was stirred for 1 h at ambienttemperature. The solvent was removed and the residue was partitionedbetween saturated aqueous sodium bicarbonate (30 mL) and ethyl acetate(20 mL). The organic phase was separated, dried over anhydrous sodiumsulfate, filtered and concentrated. The crude residue was purified bysilica gel column chromatography eluting with 5:1 DCM/MeOH to afford thetitle compound as a white solid (77 mg, 71%). MS (ESI): m/z=374.2[M+H]⁺.

Example 8 6-(1-acryloylpiperidin-3-yl)-2-(4-phenoxyphenyl)nicotinamide

To a solution of 2-(4-phenoxyphenyl)-6-(piperidin-3-yl)nicotinamide 9(19 mg, 0.05 mmol) in DCM (5 mL) was added TEA (0.05 mL, 0.4 mmol) andacryloyl chloride 10 (5 mg, 0.05 mmol) at 0° C. The mixture was stirredat 0° C. for 10 minutes. The solvent was removed and the residue waspurified by Prep-TLC eluting with 25:1 DCM/MeOH to afford the titlecompound (7 mg, 34%) as white solid. ¹H NMR (300 MHz, CDCl₃) δ 7.97 (d,J=8.9 Hz, 1H), 7.69 (d, J=8.1 Hz, 2H), 7.38 (t, J=7.8 Hz, 2H), 7.24-7.15(m, 2H), 7.12-7.01 (m, 4H), 6.62 (dd, J=16.6, 10.6 Hz, 1H), 6.28 (d,J=16.4 Hz, 1H), 5.75-5.60 (m, 2H), 5.46 (s, 1H), 4.89-4.55 (m, 1H),4.30-3.90 (m, 1H), 3.50 (t, J=12.2 Hz, 0.5H), 3.24-3.06 (m, 1H), 2.99(d, J=10.7 Hz, 1H), 2.80 (t, J=12.2 Hz, 0.5H), 2.13 (s, 1H), 1.87 (d,J=13.4 Hz, 2H), 1.64 (s, 1H). MS (ESI, method A): m/z=428.0 [M+H]⁺,t_(R)=1.526 min., HPLC: 93.3% (214 nm), 99.8% (254 nm).

tert-butyl 1-(6-chloro-5-cyanopyridin-2-yl)piperidin-4-ylcarbamate (3)

To a solution of 2,6-dichloronicotinonitrile 1 (346 mg, 2.0 mmol) inethanol (10 mL) was added tert-butyl piperidin-4-ylcarbamate 2 (400 mg,2.0 mmol) and K₂CO₃ (552 mg, 4.0 mmol). The mixture was heated to refluxstirred for 4 h. After cooling to room temperature, the solvent wasevaporated and the crude product was purified by silica gel columnchromatography eluting with 20:1 to 5:1 PE/EA to afford the titlecompound as a white solid (470 mg, 70%). MS (ESI, method A): m/z=337.2[M+H]⁺.

6-(4-aminopiperidin-1-yl)-2-chloronicotinamide (4)

To tert-butyl 1-(6-chloro-5-cyanopyridin-2-yl) piperidin-4-ylcarbamate 3(470 mg, 1.4 mmol) was added H₂SO₄ (con., 5 mL) and water (1 mL). Themixture was heated to 90° C. and stirred for 1 h. After cooling to roomtemperature, the solution was poured into ice-cold water, then adjustedto PH=8 with ammonia water. The precipitate was filtered, washed withwater (10 mL) and dried under vacuum to afford the title compound as awhite solid (340 mg, 96%). MS (ESI): m/z=255.0 [M+H]⁺.

6-(4-aminopiperidin-1-yl)-2-(4-phenoxyphenyl)nicotinamide (6)

To a solution of 6-(4-aminopiperidin-1-yl)-2-chloronicotinamide 4 (51mg, 0.2 mmol), K₂CO₃ (55 mg, 0.4 mmol) and 4-phenoxyphenylboronic acid 5(43 mg, 0.2 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was addedPd(dppf)Cl₂ (18 mg, 0.02 mmol) under nitrogen atmosphere, and themixture was degassed with nitrogen 6 times, then heated to 90° C. andstirred for 5 h under nitrogen atmosphere. After cooling to roomtemperature, the solvent was evaporated and the crude product waspurified by silica gel column chromatography eluting with 70:1 DCM/MeOHto afford the title compound as a white solid (24 mg, 310%). MS (ESI):m/z=389.2 [M+H]⁺.

Example 9 6-(4-acrylamidopiperidin-1-yl)-2-(4-phenoxyphenyl)nicotinamide

To a solution of6-(4-aminopiperidin-1-yl)-2-(4-phenoxyphenyl)nicotinamide 6 (62 mg, 0.16mmol) in DCM (5 mL) was added TEA (0.05 mL, 0.4 mmol) and acryloylchloride 7 (15 mg, 0.16 mmol) at 0° C. The mixture was stirred at 0° C.for 10 minutes. The solvent was removed and the residue was purified byPrep-TLC eluting with 25:1 DCM/MeOH to afford the title compound (14 mg,20%) as white solid. ¹H NMR (300 MHz, CDCl₃) δ 7.98 (d, J=8.8 Hz, 1H),7.62 (d, J=8.5 Hz, 2H), 7.38 (t, J=7.8 Hz, 2H), 7.16 (t, J=7.4 Hz, 1H),7.12-7.00 (m, 4H), 6.65 (d, J=8.9 Hz, 1H), 6.31 (d, J=16.9 Hz, 1H), 6.07(dd, J=16.9, 10.2 Hz, 1H), 5.66 (d, J=10.2 Hz, 1H), 5.52-5.48 (m, 1H),5.28 (s, 1H), 4.44 (d, J=13.4 Hz, 2H), 4.24-4.08 (m, 1H), 3.08 (t,J=11.9 Hz, 2H), 2.08 (d, J=10.7 Hz, 2H), 1.62 (s, 1H), 1.47 (dt, J=11.3,6.1 Hz, 2H). MS (ESI, method A): m/z=443.2 [M+H]⁺, t_(R)=1.434 min.,HPLC: 99.1% (214 nm), 99.3% (254 nm).

tert-butyl 1-(6-chloro-5-cyanopyridin-2-yl)pyrrolidin-3-ylcarbamate (3)

To a solution of 2, 6-dichloronicotinonitrile 1 (346 mg, 2.0 mmol) inethanol (10 mL) was added tert-butyl piperidin-4-ylcarbamate 2 (372 mg,2.0 mmol) and K₂CO₃ (552 mg, 4.0 mmol). The mixture was heated to refluxand stirred for 4 h. After cooling to room temperature, the solvent wasevaporated and the crude product was purified by silica gel columnchromatography eluting with 20:1 to 5:1 PE/EA to afford the titlecompound as a white solid (365 mg, 57%). MS (ESI, method A): m/z=345.1[M+Na]⁺.

6-(4-aminopiperidin-1-yl)-2-chloronicotinamide (4)

To tert-butyl 1-(6-chloro-5-cyanopyridin-2-yl) pyrrolidin-3-ylcarbamate3 (357 mg, 1.1 mmol) was added H₂SO₄ (conc., 5 mL) and water (1 mL). Themixture was heated to 90° C. and stirred for 1 h. After cooling to roomtemperature, the solution was poured into ice-cold water, then adjustedto PH=8 with ammonia water. The precipitate was filtered, washed withwater (10 mL) and dried under vacuum to afford the title compound asbrown solid (192 mg, 72%). MS (ESI, method A): m/z=241.0 [M+H]⁺.

6-(3-aminopyrrolidin-1-yl)-2-(4-phenoxyphenyl)nicotinamide (6)

To a solution of 6-(4-aminopiperidin-1-yl)-2-chloronicotinamide 4 (192mg, 0.79 mmol), K₂CO₃ (220 mg, 1.6 mmol) and 4-phenoxyphenylboronic acid5 (171 mg, 0.8 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was addedPd(dppf)Cl₂ (69 mg, 0.08 mmol) under nitrogen atmosphere, and themixture was degassed with nitrogen 6 times, then heated to 90° C. andstirred for 5 h under nitrogen atmosphere. After cooling to roomtemperature, the solvent was evaporated and the crude product waspurified by flash chromatography eluting with 70:1 DCM/MeOH to affordthe title compound as a white solid (92 mg, 31%). MS (ESI): m/z=375.2[M+H]⁺.

Example 106-(3-acrylamidopyrrolidin-1-yl)-2-(4-phenoxyphenyl)nicotinamide

To a solution of6-(3-aminopyrrolidin-1-yl)-2-(4-phenoxyphenyl)nicotinamide 6 (92 mg,0.25 mmol) in DCM (5 mL) was added TEA (0.14 mL, 1.0 mmol) and acryloylchloride 7 (23 mg, 0.25 mmol) at 0° C. The mixture was stirred at 0° C.for 10 minutes. The solvent was removed and the residue was purified byPrep-TLC eluting with 25:1 DCM/MeOH to afford the title compound (58 mg,54%) as white solid. ¹H NMR (300 MHz, CDCl₃) δ 7.95 (d, J=8.7 Hz, 1H),7.62 (d, J=8.5 Hz, 2H), 7.38 (t, J=7.8 Hz, 2H), 7.16 (t, J=7.4 Hz, 1H),7.05 (dd, J=12.6, 8.3 Hz, 4H), 6.40-625 (m, 1H), 6.10 (dd, J=16.8, 10.2Hz, 2H), 5.67 (d, J=10.2 Hz, 1H), 5.48 (s, 1H), 5.31 (s, 1H), 4.71 (d,J=4.4 Hz, 1H), 3.85 (dd, J=11.2, 6.0 Hz, 1H), 3.75-340 (m, 4H),2.40-2.25 (m, 1H), 2.10-1.90 (m, 1H). MS (ESI, method A): m/z=429.0[M+H]⁺, t_(R)=1.443 min., HPLC: 100% (214 nm), 100% (254 nm).

Example 111-(1-acryloylpiperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide

Refer to Example 34 schemes and associated experimental procedures anddata described below.

Example 121-(1-acryloylpiperidin-4-yl-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide

Refer to Example 34 schemes and associated experimental procedures anddata described below.

Example 131-(1-acryloylpyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide

Refer to Example 34 schemes and associated experimental procedures anddata described below.

Example 141-(azetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide

Refer to Example 34 scheme and associated experimental procedures anddata described below.

tert-butyl 3-(tosyloxy)azetidine-1-carboxylate (2)

To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate 1 (2.0 g,11.5 mmol) in pyridine (25 mL) was added TsCl (2.64 g, 13.8 mmol), andthe resulting solution was stirred for 16 h at rt. The solvent wasevaporated and the crude residue was purified by silica gel column,eluting with 5:1 petroleum ether/ethyl acetate to afford the titlecompound (3.2 g, 85%) as colorless oil. MS (ESI): m/z=350.0 [M+Na]⁺.

Ethyl-1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate(4)

To a solution of tert-butyl 3-(tosyloxy)azetidine-1-carboxylate 2 (1.3g, 3.88 mmol) and CsCO₃ (2.12 g, 6.48 mmol) in DMF (25 mL) was addedethyl 3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate 3 (1.0 g, 3.24mmol), and the resulting solution was stirred for 16 h at 100° C. Thesolvent was evaporated and the crude residue was purified by silica gelcolumn eluting with 3:1 petroleum ether/ethyl acetate to afford thetitle compound (1.39 g, 93%) as white solid. MS (ESI): m/z=464.0 [M+H]⁺.

1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylicacid (5)

To a solution of ethyl1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate4 (1.39 g, 3.0 mmol) in EtOH (20 mL) and water (2 mL) was added LiOH(630 mg, 15.0 mmol), and the resulting solution was stirred for 16 h atit. The solvent was evaporated, and the residue was dissolved in water(5 mL) and the resulting solution was acidified with 2 N hydrochloricacid to pH=6. The precipitate was filtered, washed with water (15 mL)and dried under vacuum to afford the title compound (1.2 g, 92%) as awhite solid. MS (ESI): m/z=436.0 [M+H]⁺.

tert-butyl-3-(4-carbamoyl-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(6)

To a solution of1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylicacid 5 (800 mg, 1.84 mmol), NH₄Cl (120 mg, 2.21 mmol) and HATU (1.04 mg,2.76 mmol) in dry DMF (10 mL) was added DIPEA (957 mg, 7.36 mmol), andthe resulting solution was stirred overnight at rt. After the reactionwas completed, the solution was concentrated, diluted with ethyl acetate(30 mL) and washed with water (2×20 mL) and brine (2×20 mL). The organiclayer was dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel column eluting with40:1 DCM/MeOH to afford the title compound (700 mg, 82%) as white solid.MS (ESI): m/z=435.0 [M+H]⁺.

1-(azetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (7)

To a solution of3-(4-carbamoyl-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)azetidine-1-carboxylate6 (700 mg, 1.61 mmol) in DCM (20 mL) was added conc. HCl (5 mL) and thereaction mixture was stirred at rt for 1 h. After the reaction wascompleted, the solution was concentrated to afford the title compound(600 mg, 100%) as white solid. MS (ESI): m/z=335.0 [M+H]⁺.

Example 151-(1-acryloylazetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide

To a solution of1-(azetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide 7 (300mg, 0.81 mmol) in dry DCM (15 mL) were added DIEA (316 mg, 2.43 mmol)and acryloyl chloride (88 mg, 0.97 mmol) at 0° C., and the resultingsolution was stirred at 0° C. for 10 min. Water (10 mL) was added toquench the reaction. The mixture was diluted with DCM (20 mL), andwashed with water (2×20 mL) and brine (2×20 mL). The organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated. Theresidue was purified by Prep-HPLC (ACN-H₂O=20-70, 0.1% FA) to afford thetitle compound (160 mg, 51%) as a white solid. ¹H NMR (400 MHz, DMSO) δ8.38 (s, 1H), 7.81 (d, J=8.7 Hz, 2H), 7.47-7.38 (m, 3H), 7.20-7.14 (m,1H), 7.11-6.99 (m, 5H), 6.43-6.34 (m, 1H), 6.20-6.12 (m, 1H), 5.76-5.70(m, 1H), 5.38-5.29 (m, 1H), 4.78-4.68 (m, 1H), 4.59-4.49 (m, 1H),4.48-4.40 (m, 1H), 4.32-4.22 (m, 1H). MS (ESI, Method A): m/z=389.1[M+H]⁺, t_(R)=1.374 min. HPLC: 99.7% (214 nm), 99.7% (254 nm).

Example 161-(4-acrylamidophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide

Refer to Example 34 schemes and associated experimental procedures anddata described below.

Example 171-(3-aminophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide

Refer to Example 34 schemes and associated experimental procedures anddata described below.

Example 181-(3-acrylamidophenyl)-3-(4-phenoxyphenyl-1H-pyrazole-4-carboxamide

Refer to Example 34 schemes and associated experimental procedures anddata described below.

Example 19(S)-1-(1-acryloylpyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide

Refer to Example 34 schemes and associated experimental procedures anddata described below.

Refer to Example 34 schemes and associated experimental procedures anddata described below.

2,4-dichloropyrimidine-5-carbonyl chloride (2)

To a solution of 2,4-dihydroxypyrimidine-5-carboxylic acid (5.0 g, 32.0mmol) in POCl₃ (50 mL) was added PCl₅(23.9 g, 115.2 mmol), and theresulting solution was heated to 115° C. and stirred for 12 h. Thesolvent was evaporated and the crude residue was diluted with ethylacetate (100 mL). The solid was filtered and the filtrate wasconcentrated to give the title compound as brown oil (6.2 g, 92%).

2,4-dichloropyrimidine-5-carboxamide (3)

To a solution of 2,4-dichloropyrimidine-5-carbonyl chloride (6.2 g, 29.3mmol) in 1,4-dioxane (50 mL) was added ammonia (1.0 g, 58.3 mmol) in1,4-dioxane (50 mL) dropwise at 0° C., and the resulting solution wasstirred for 12 h at ambient temperature. The mixture was diluted withethyl acetate (50 mL), and washed with water (2×80 mL) and brine (2×80mL). The organic layer was dried over anhydrous sodium sulfate, filteredand concentrated to afford the title compound as a white solid (4.5 g,80%). MS (ESI): m/z=191.8 [M+H]⁺.

2-chloro-4-(4-phenoxyphenyl)pyrimidine-5-carboxamide (4)

To a solution of 4-phenoxyphenylboronic acid (1.0 g, 4.7 mmol), K₂CO₃(1.4 g, 10.4 mmol) and 2,4-dichloropyrimidine-5-carboxamide (1.0 g, 5.2mmol) in 1,4-dioxane (24 mL) and water (3 mL) was added Pd(dppf)Cl₂ (380mg, 0.52 mmol) under nitrogen atmosphere, and the mixture was degassedwith nitrogen 6 times, then heated to 60° C. and stirred for 3 h undernitrogen atmosphere. After cooling to room temperature, the solution waspoured into water (50 mL), and then extracted with ethyl acetate (3×40mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated. The crude product was purified bycolumn chromatography, eluting with 100:1 dichloromethane/methanol toafford the title compound as a brown solid (410 mg, 24%). MS (ESI):m/z=325.9 [M+H]⁺.

tert-butyl4-(5-carbamoyl-4-(4-phenoxyphenyl)pyrimidin-2-yl)-5,6-dihydropyridine-1(2H)carboxylate (6)

To a solution of 2-chloro-4-(4-phenoxyphenyl)pyrimidine-5-carboxamide 4(410 mg, 1.26 mmol), K₂CO₃ (521.6 mg, 3.78 mmol) and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate5 (583 mg, 1.89 mmol) in DME (30 mL) and water (5 mL) was addedPd(PPh₃)₄(146 mg, 0.126 mmol) under nitrogen atmosphere, and the mixturewas degassed with nitrogen 6 times, and then heated to 85° C. andstirred for 12 h under nitrogen atmosphere. After cooling to roomtemperature, the solvent was evaporated and the crude product waspurified by flash chromatography eluting with 80:1 DCM/MeOH to affordthe title compound as a brown solid (420 mg, 71%). MS (ESI): m/z=472.8[M+H]⁺.

tert-butyl4-(5-carbamoyl-4-(4-phenoxyphenyl)pyrimidin-2-yl)piperidine-1-carboxylate(7)

To a solution of tert-butyl4-(5-carbamoyl-4-(4-phenoxyphenyl)pyrimidin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate6 (100 mg, 0.212 mmol) in ethyl acetate (5 mL) was added Pd/C (20 mg)under hydrogen atmosphere, and the mixture was degassed with hydrogen 6times, then stirred for 16 h at ambient temperature under hydrogenatmosphere. The solution was filtered and the filtrate was evaporated tothe crude product as brown solid (96 mg). MS (ESI): m/z=474.8 [M+H]⁺.

4-(4-phenoxyphenyl)-2-(piperidin-4-yl)pyrimidine-5-carboxamide (8)

To a solution of tert-butyl4-(5-carbamoyl-4-(4-phenoxyphenyl)pyrimidin-2-yl)piperidine-1-carboxylate 7 (96 mg, crude) in dry dichloromethane (2 mL)was added TFA (2 mL), and the resulting mixture was stirred for 1 h atambient temperature. The solvent was removed and the residue waspartitioned between saturated aqueous sodium bicarbonate (30 mL) andethyl acetate (20 mL). The organic phase was separated, dried overanhydrous sodium sulfate, filtered and concentrated. The crude residuewas purified by flash chromatography, eluting with 5:1 DCM/MeOH toafford the title compound as a white solid (70 mg, 88% for two steps).MS (ESI): m/z=374.9 [M+H]⁺.

Example 212-(1-acryloylpiperidin-4-yl)-4-(4-phenoxyphenyl)pyrimidine-5-carboxamide

To a solution of4-(4-phenoxyphenyl)-2-(piperidin-4-yl)pyrimidine-5-carboxamide 8 (70 mg,0.187 mmol) in DCM (3 mL) was added TEA (56.7 mg, 0.56 mmol) andacryloyl chloride (25.3 mg, 0.28 mmol) at 0° C. The mixture was stirredat 0° C. for 10 min. The solvent was removed and the residue waspurified by Prep-TLC eluting with 25:1 DCM/MeOH to afford the titlecompound (50 mg, 63%) as light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ8.95 (s, 1H), 7.82 (d, J=8.8 Hz, 2H), 7.49-7.36 (m, 2H), 7.27-7.17 (m,1H), 7.16-7.04 (m, 4H), 6.64 (dd, J=16.8, 10.6 Hz, 1H), 6.29 (dd,J=16.8, 1.9 Hz, 1H), 5.94 (s, 1H), 5.77 (s, 1H), 5.71 (dd, J=10.6, 1.9Hz, 1H), 4.76 (d, J=12.5 Hz, 1H), 4.14 (d, J=14.1 Hz, 1H), 3.37-3.19 (m,2H), 2.89 (t, J=11.5 Hz, 1H), 2.16 (d, J=11.0 Hz, 2H), 1.97 (d, J=9.9Hz, 2H). MS (ESI, method F): m % z=428.8 [M+H]⁺, t_(R)=1.407 min., HPLC:99.8% (214 nm), 99.6% (254 nm).

1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yltrifluoromethanesulfonate (2)

To a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate 1 (5.0 g,27.0 mmol) in tetrahydrofuran (130 mL) in a three-necked flask was addedlithium diisopropylamide (2.0M, 16.2 mL, 32.4 mmol) at −78° C. Afterstirring for 2 h at −78° C., a solution oftrifluoro-N-phenyl-N-(trifluoromethylsulfonyl) methanesulfonamide (10.1g, 28.4 mmol) in tetrahydrofuran (20 mL) was added, and the solution wasstirred for another 30 min at this temperature, then warmed to roomtemperature and stirred for 3 h. Water (30 mL) was added to quench thereaction, and the solution was extracted with ethyl acetate (3×200 mL).The organic layers were combined, dried over anhydrous sodium sulfate,filtered and concentrated. The residue was purified by silica gel columnchromatography, eluting with petroleum ether to afford the titlecompound as a brown oil (4.2 g, 49%). MS (ESI): m/z=318.1 [M+H]⁺.

tert-butyl-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-pyrrole-1(5H)-carboxylate(3)

To a solution of bis(pinacolato)diborone (4.0 g, 15.9 mmol), KOAc (2.59g, 26.4 mmol) and 1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yltrifluoromethanesulfonate 2 (4.2 g, 13.2 mmol) in dry 1,4-dioxane (10mL) was added Pd(dppf)Cl₂ (965 mg, 1.32 mmol) under nitrogen atmosphere,and the mixture was degassed with nitrogen 6 times, then heated to 85°C. and stirred overnight under nitrogen atmosphere. After cooling toroom temperature, the solvent was evaporated and the crude product waspurified by silica gel column chromatography, eluting from 100:1 to 20:1petroleum ether/ethyl acetate to afford the title compound as brown oil(1.2 g, 31%). MS (ESI): m/z=296.1 [M+H]⁺.

tert-butyl-3-(5-carbamoyl-4-(4-phenoxyphenyl)pyrimidin-2-yl)-2H-pyrrole-1(5H)-carboxylate(5)

To a solution of tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-pyrrole-1(5H)-carboxylate3 (136 mg, 0.46 mmol), K₂CO₃ (127 mg, 0.92 mmol) and2-chloro-4-(4-phenoxyphenyl)pyrimidine-5-carboxamide 4 (100 mg, 0.31mmol) in 1,4-dioxane (15 mL) and water (3 mL) was added Pd(PPh₃)₄(35.5mg, 0.031 mmol) under nitrogen atmosphere. The mixture was degassed withnitrogen 6 times, then heated to 90° C. and stirred for 12 h undernitrogen atmosphere. After cooling to room temperature, the solvent wasevaporated and the crude product was purified by flash chromatographyeluting with 70:1 DCM/MeOH to afford the title compound as a white solid(90 mg, 64%). MS (ESI): m/z=458.8 [M+H]⁺.

tert-butyl-3-(5-carbamoyl-4-(4-phenoxyphenyl)pyrimidin-2-yl)pyrrolidine-1-carboxylate(6)

To a solution of tert-butyl3-(5-carbamoyl-4-(4-phenoxyphenyl)pyrimidin-2-yl)-2H-pyrrole-1(5H)-carboxylate5 (90 mg, 0.20 mmol) in ethyl acetate (3 mL) and MeOH (3 mL) was addedPd/C (20 mg) under hydrogen atmosphere, and the mixture was degassedwith hydrogen 6 times, then stirred for 16 h at ambient temperatureunder hydrogen atmosphere. The solution was filtered and the filtratewas evaporated to the crude product as brown solid (80 mg, 88%). MS(ESI): m/z=461.1 [M+H]⁺.

4-(4-phenoxyphenyl)-2-(pyrrolidin-3-yl)pyrimidine-5-carboxamide (7)

To a solution of tert-butyl3-(5-carbamoyl-4-(4-phenoxyphenyl)pyrimidin-2-yl)pyrrolidine-1-carboxylate6 (80 mg, 0.174 mmol) in dry dichloromethane (2 mL) was added TFA (2mL), and the resulting mixture was stirred for 1 h at ambienttemperature. The solvent was removed and the residue was partitionedbetween saturated aqueous sodium bicarbonate (30 mL) and ethyl acetate(20 mL). The organic phase was separated, dried over anhydrous sodiumsulfate, filtered and concentrated to afford the title compound as awhite solid (70 mg, crude). MS (ESI): m/z=360.8 [M+H]⁺.

Example 222-(1-acryloylpyrrolidin-3-yl)-4-(4-phenoxyphenyl)pyrimidine-5-carboxamide

To a solution of4-(4-phenoxyphenyl)-2-(pyrrolidin-3-yl)pyrimidine-5-carboxamide 7 (70mg, crude) in DCM (5 mL) was added TEA (59 mg, 0.58 mmol) and acryloylchloride (26 mg, 0.29 mmol) at 0° C. The mixture was stirred at 0° C.for 10 min. The solvent was removed and the residue was purified byPrep-TLC eluting with 25:1 DCM/MeOH to afford the title compound (20 mg,25%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.95 (d, J=6.2 Hz, 1H),7.82 (d, J=6.6 Hz, 2H), 7.42 (t, J=7.8 Hz, 2H), 7.22 (t, J=7.4 Hz, 1H),7.10 (t, J=7.9 Hz, 4H), 6.55-6.47 (m, 1H), 6.39 (d, J=16.8, Hz, 1H),5.84 (s, 2H), 5.71 (d, J=10.1 Hz, 1H), 4.14-3.96 (m, 2H), 3.94-3.78 (m,2H), 3.76-3.62 (m, 1H), 2.55-2.36 (m, 2H). MS (ESI, method F): m/z=414.8[M+H]⁺, t_(R)=1.382 min., HPLC: 99.0% (214 nm), 98.4% (254 nm).

tert-butyl-3-(5-carbamoyl-6-(4-phenoxyphenyl)pyridin-2-yl)-2H-pyrrole-1(5H)-carboxylate (3)

To a solution of tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-pyrrole-1(5H)-carboxylate1 (136 mg, 0.0.46 mmol), K₂CO₃ (127.5 mg, 0.92 mmol) and6-chloro-2-(4-phenoxyphenyl) nicotinamide 2 (100 mg, 0.31 mmol) in1,2-dimethoxyethane (5 mL) and water (1 mL) was added Pd(PPh₃)₄ (35.6mg, 0.031 mmol) under nitrogen atmosphere, and the mixture was degassedwith nitrogen 6 times, then heated to 85° C. and stirred for 12 h undernitrogen atmosphere. After cooling to room temperature, the solvent wasevaporated and the crude product was purified by flash chromatography,eluting with 50:1 DCM/MeOH to afford the title compound as a white solid(84 mg, 60%). MS (ESI): m/z=458.1 [M+H]⁺.

tert-butyl3-(5-carbamoyl-6-(4-phenoxyphenyl)pyridin-2-yl)pyrrolidine-1-carboxylate(4)

To a solution of tert-butyl3-(5-carbamoyl-6-(4-phenoxyphenyl)pyridin-2-yl)-2H-pyrrole-1(5H)-carboxylate3 (84 mg, 0.18 mmol) in ethyl acetate (5 mL) and MeOH (5 mL) was addedPd/C (40 mg) under hydrogen atmosphere, and the mixture was degassedwith hydrogen 6 times, then stirred for 12 h at ambient temperatureunder hydrogen atmosphere. The solution was filtered and the filtratewas evaporated to the crude product as brown solid (80 mg, 95%). MS(ESI): m/z=459.8 [M+H]⁺.

2-(4-phenoxyphenyl)-6-(pyrrolidin-3-yl)pyridine-3-carboxamide (5)

To a solution of tert-butyl3-(5-carbamoyl-6-(4-phenoxyphenyl)pyridin-2-yl)pyrrolidine-1-carboxylate4 (80 mg, 0.17 mmol) in dry dichloromethane (2 mL) was added TFA (2 mL),and the resulting mixture was stirred for 1 h at ambient temperature.The solvent was removed and the residue was partitioned betweensaturated aqueous sodium bicarbonate (30 mL) and ethyl acetate (20 mL).The organic phase was separated, dried over anhydrous sodium sulfate,filtered and concentrated to afford the title compound as a white solid(70 mg, crude). MS (ESI): m/z=359.9 [M+H]⁺.

Example 236-(1-acryloylpyrrolidin-3-yl)-2-(4-phenoxyphenyl)pyridine-3-carboxamide

To a solution of2-(4-phenoxyphenyl)-6-(pyrrolidin-3-yl)pyridine-3-carboxamide 5 (70 mg,crude) in DCM (5 mL) was added TEA (59 mg, 0.58 mmol) and acryloylchloride (26.4 mg, 0.29 mmol) at 0° C. The mixture was stirred at 0° C.for 10 min. The solvent was removed and the residue was purified byPrep-TLC eluting with 25:1 DCM/MeOH to afford the title compound (18 mg,25% for two steps) as white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.06 (s,1H), 7.72 (s, 2H), 7.41 (t, J=7.8 Hz, 2H), 7.28-7.24 (m, 1H), 7.19 (t,J=7.4 Hz, 1H), 7.11-7.09 (m, 4H), 6.55-6.47 (m, 1H), 6.41 (d, J=16.8,Hz, 1H), 5.71 (d, J=10.1 Hz, 1H), 5.65 (br, 1H), 5.45 (br, 1H),4.14-3.96 (m, 1H), 3.94-3.78 (m, 2H), 3.76-3.62 (m, 2H), 2.55-2.36 (m,2H). MS (ESI, method F): m/z=413.8 [M+H]⁺, t_(R)=1.393 min., HPLC: 97.3%(214 nm), 99.5% (254 nm).

2-(4-phenoxyphenyl)-6-(piperidin-4-yl)pyridine-3-carbonitrile (2)

A solution of tert-butyl4-(5-carbamoyl-4-(4-phenoxyphenyl)pyrimidin-2-yl)piperidine-1-carboxylate(100 mg, 0.21 mmol) in POCl₃ (3 mL) was heated to 100° C. and stirredfor 3 h. After cooling to room temperature, the reaction mixture waspoured into water (3 mL), and basified by saturate aqueous NaHCO₃ toPH=10. Then the solution was extracted with ethyl acetate (3×60 mL). Theorganic layers were combined, dried over anhydrous sodium sulfate,filtered and concentrated. The crude residue was purified by preparativeTLC eluting with 8:1 DCM/MeOH to afford the title compound as brown oil(10 mg, 13%). MS (ESI): m/z=356.1 [M+H]⁺.

Example 246-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)pyridine-3-carbonitrile

To a solution of2-(4-phenoxyphenyl)-6-(piperidin-4-yl)pyridine-3-carbonitrile 2 (10 mg,0.028 mmol) in DCM (2 mL) was added TEA (8.5 mg, 0.084 mmol) andacryloyl chloride (3.8 mg, 0.042 mmol) at 0° C. The mixture was stirredat 0° C. for 10 min. The solvent was removed and the residue waspurified by Prep-TLC eluting with 25:1 DCM/MeOH to afford the titlecompound (13 mg, 44%) as white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.01 (d,J=8.1 Hz, 1H), 7.97 (dd, J=9.2, 2.3 Hz, 2H), 7.41 (t, J=7.9 Hz, 2H),7.24-7.17 (m, 2H), 7.16-7.09 (m, 4H), 6.64 (dd, J=16.8, 10.6 Hz, 1H),6.32 (dd, J=16.8, 1.8 Hz, 1H), 5.73 (dd, J=10.6, 1.9 Hz, 1H), 4.85-4.79(m, 1H), 4.21-4.16 (m, 1H), 3.25-4.18 (m, 1H), 3.12 (tt, J=12.0, 3.8 Hz,1H), 2.84-2.78 (m, 1H), 2.09-2.06 (m, 2H), 1.93-1.82 (m, 2H). MS (ESI,method F): m/z=409.8 [M+H], t_(R)=1.669 min., HPLC: 98.7% (214 nm),98.8% (254 nm).

tert-butyl 4-(6-chloro-5-cyanopyridin-2-yl)piperazine-1-carboxylate (3)

To a solution of 2,6-dichloronicotinonitrile 1 (1.0 g, 5.78 mmol) andtert-butyl piperazine-1-carboxylate 2 (1.08 g, 5.78 mmol) in ethanol (20mL) was added K₂CO₃ (636 mg, 6.0 mmol). The resulting solution wasrefluxed for 3 h. After cooling to room temperature, the solvent wasevaporated and the crude product was purified by flash chromatographyeluting from 5:1 to 2:1 PE/EA to afford the title compound as a whitesolid (800 mg, 43%). MS (ESI): m/z=345.1 [M+Na]⁺.

6-chloro-2-(4-phenoxyphenyl)nicotinamide (4)

To tert-butyl-(6-chloro-5-cyanopyridin-2-yl)piper azine-1-carboxylate3(800 mg, 2.5 mmol) was added conc. H₂SO₄ (5 mL) and water (1 mL). Themixture was heated to 90° C. and stirred for 40 min. After cooling toroom temperature, the solution was poured into ice-cold water, thenadjusted to PH=8 by ammonia water. The precipitate was filtered, washedwith water (20 mL) and dried under vacuum to afford the title compoundas an off-white solid (580 mg, 96%). MS (ESI): m/z=241.1 [M+H]⁺.

2-(4-phenoxyphenyl)-6-(piperazin-1-yl)nicotinamide (6)

To a solution of 6-chloro-2-(4-phenoxyphenyl)nicotinamide 4 (580 mg,2.41 mmol), Cs₂CO₃ (2.35 g, 7.23 mmol) and 4-phenoxyphenylboronic acid 5(619 mg, 2.89 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was addedPd₂(dba)₃ (220 mg, 0.24 mmol) under nitrogen atmosphere, and the mixturewas degassed with nitrogen 6 times, then heated to 90° C. and stirredfor 12 h under nitrogen atmosphere. After cooling to room temperature,the solvent was evaporated and the crude product was purified by flashchromatography eluting with 10:1 DCM/MeOH to afford the title compoundas a white solid (480 mg, 52%). MS (ESI): m/z=375.1 [M+H]⁺.

Example 25(E)-6-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)-2-(4-phenoxyphenyl)nicotinamide

A mixture of 2-(4-phenoxyphenyl)-6-(piperazin-1-yl)nicotinamide 6 (100mg, 0.27 mmol), (E)-4-(dimethylamino)but-2-enoic acid hydrochloride 7(53 mg, 0.32 mmol), HATU (152 mg, 0.4 mmol), and DIPEA (172.5 mg, 1.34mmol) in DMF (10 mL) was stirred at rt for 12 h. The solution was pouredinto water (50 mL), and then extracted with ethyl acetate (3×50 mL). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated. The residue was purified by Prep-TLC elutingwith 10:1 DCM/MeOH to afford the title compound (30 mg, 23%) as a whitesolid. ¹H NMR (400 MHz, MeOD) δ 7.78 (d, J=8.7 Hz, 1H), 7.69 (d, J=8.6Hz, 2H), 7.40 (t, J=7.9 Hz, 2H), 7.17 (d, J=7.4 Hz, 1H), 7.04 (dd,J=15.3, 8.3 Hz, 4H), 6.93 (d, J=15.3 Hz, 1H), 6.82 (d, J=8.7 Hz, 1H),6.77 (m, 1H), 3.89-3.68 (m, 10H), 2.76 (s, 6H). MS (ESI, method F):m/z=485.9 [M+H]⁺, t_(R)=1.249 min., HPLC: 93.3% (214 nm), 93.0% (254nm).

2-(4-phenoxyphenyl)-6-(piperazin-1-yl)nicotinamide (3)

To a solution of tert-butyl4-(6-chloro-5-cyanopyridin-2-yl)piperazine-1-carboxylate 1 (300 mg, 0.93mmol), K₂CO₃ (385 mg, 2.79 mmol) and 4-phenoxyphenylboronic acid 2 (297mg, 1.39 mmol) in 1,4-dioxane (12 mL) and water (2 mL) was addedPd(dppf)Cl₂ (68 mg, 0.093 mmol) under nitrogen atmosphere. The mixturewas degassed with nitrogen 6 times, then heated to 90° C. and stirredfor 12 h under nitrogen atmosphere. After cooling to room temperature,the solvent was evaporated and the crude product was purified by flashchromatography eluting with 20:1 DCM/MeOH to afford the title compoundas a white solid (260 mg, 58%). MS (ESI): m/z=457.1 [M+H]⁺.

2-(4-phenoxyphenyl)-6-(piperazin-1-yl)nicotinic acid hydrochloride (4)

In a 20 mL sealed tube, was placed a solution of2-(4-phenoxyphenyl)-6-(piperazin-1-yl)nicotinamide 3 (140 mg, 0.31 mmol)in conc. HCl (5 mL). The mixture was heated to 115° C. and stirred for 4h. After cooling to room temperature, the solution was concentratedunder vacuum to afford the title compound as an off-white solid (120 mg,95%). MS (ESI): m/z=376.1 [M+H]⁺.

Example 266-(4-acryloylpiperazin-1-yl)-2-(4-phenoxyphenyl)pyridine-3-carboxylicacid

To a solution of 2-(4-phenoxyphenyl)-6-(piperazin-1-yl)nicotinic acidhydrochloride 4 (120 mg, 0.32 mmol) in DCM (5 mL) was added TEA (162 mg,1.6 mmol) and acryloyl chloride (35 mg, 0.38 mmol) at 0° C. The mixturewas stirred at 0° C. for 10 minutes. The solvent was removed and theresidue was purified by Prep-TLC eluting with 20:1 DCM/MeOH to affordthe title compound (15 mg, 11%) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (d, J=8.9 Hz, 1H), 7.55 (d, J=8.3 Hz, 2H), 7.38 (t, J=7.7Hz, 2H), 7.16 (t, J=7.4 Hz, 1H), 7.11 (d, J=8.0 Hz, 2H), 7.03 (d, J=8.3Hz, 2H), 6.65-6.55 (m, 2H), 6.38 (d, J=16.7 Hz, 1H), 5.78 (d, J=10.6 Hz,1H), 3.86-375 (m, 8H). MS (ESI, method F): m/z=429.8 [M+H]⁺, t_(R)=1.477min., HPLC: 93.5% (214 nm), 93.0% (254 nm).

4-(4-bromophenoxy)benzonitrile (3)

The mixture of 4-bromophenol 1 (0.50 g, 2.9 mmol), 4-fluorobenzonitrile2 (0.28 g, 2.31 mmol), K₂CO₃ (0.80 g, 5.8 mmol) and DMF (4 mL) wasstirred at 115° C. for 16 h. After cooled to rt, the mixture wasconcentrated in vacuo. The residue was purified by silica gelchromatography eluting with 100:1 petroleum ether/EtOAc to afford thetitle compound (0.59 g, 74%) as white solid. ¹H NMR (400 MHz, DMSO-d6) δ7.86 (d. J=8.7 Hz, 2H), 7.64 (d, J=6.0 Hz, 2H), 7.13 (dd, J=5.1, 4.7 Hz,4H).

4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile(4)

The mixture of 4-(4-bromophenoxy)benzonitrile 3 (0.59 g, 2.15 mmol),bispinacolato diboron (1.09 g, 4.3 mmol), KOAc (0.63 g, 6.45 mmol),Pd(dppf)Cl₂ (0.157 g, 0.215 mmol) and DMF (3.5 mL) was degassed with N₂6 times and then stirred under reflux for 16 h. After cooled to rt, themixture was concentrated in vacuo. The residue was purified by silicagel chromatography eluting with 50:1 petroleum ether/EtOAc to afford thetitle compound (0.55 g, 79%) as white solid.

2-(4-(4-cyanophenoxy)phenyl)-6-(piperazin-1-yl)nicotinamide (6)

The title compound was obtained using a procedure analogous to theprocedure described in2-(4-(hydroxy(phenyl)methyl)phenyl)-6-(piperidin-4-yl)nicotinamide (seeScheme 48) as yellow solid (0.15 g, 37%). MS (ESI): m/z=400.1 [M+H]⁺.

Example 276-(4-acryloylpiperazin-1-yl)-2-(4-(4-cyanophenoxy)phenyl)nicotinamide

The title compound was obtained using a procedure analogous to theprocedure described in Example 1 as white solid (40 mg, 23%). ¹H NMR(400 MHz, DMSO-d6) δ 7.88 (d, J=8.7 Hz, 2H), 7.73 (d, J=8.6 Hz, 2H),7.68 (d, J=8.7 Hz, 1H), 7.59 (s, 1H), 7.26 (s, 1H), 7.21-7.14 (m, 4H),6.86 (dd, J=17.8, 9.3 Hz, 2H), 6.16 (dd, J=16.7, 2.2 Hz, 1H), 5.73 (dd,J=10.4, 2.2 Hz, 1H), 3.66-3.67 (m, 8H). MS (ESI, method A): m/z=454.1[M+H]⁺, t_(R)=1.685 (min). HPLC: 97.1% (214 nm), 99.7% (254 nm).

1-bromo-4-(cyclohexyloxy)benzene (3)

The mixture of 1-bromo-4-iodobenzene 1 (2.83 g, 10 mmol), cyclohexanol 2(5.0 g, 50 mmol), CuI (0.381 g, 2.0 mmol), 1,10-phenanthroline (0.793 g,4.0 mmol), Cs₂CO₃ (8.15 g, 25 mmol) and toluene (5 mL) was stirred at120° C. in a sealed tube under N₂ for 16 h. After cooled to rt, themixture was filtered over celite. The filtrate was dried over Na₂SO₄,concentrated in vacuo and purified by silica gel chromatography elutingwith 20:1 petroleum ether/EtOAc to afford the title compound (1.17 g,46%) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.33 (m, 2H),6.83-6.77 (m, 2H), 4.26-4.16 (m, 1H), 2.04-1.92 (m, 2H), 1.87-1.75 (m,2H), 1.65-1.47 (m, 3H), 1.45-1.25 (m, 3H).

2-(4-(cyclohexyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4)

The title compound was obtained using a procedure analogous to theprocedure described in4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile(see Scheme 16) as brown oil (1.04 g, 75%). ¹H NMR (400 MHz, CDCl₃) δ7.75 (d, J=8.5 Hz, 2H), 6.91 (d, J=8.5 Hz, 2H), 4.40-4.25 (m, 1H),2.09-1.94 (m, 2H), 1.89-1.76 (m, 2H), 1.66-1.49 (m, 4H), 1.48-1.23 (m,14H).

2-(4-(cyclohexyloxy)phenyl)-6-(piperazin-1-yl)nicotinamide (6)

The title compound was obtained using a procedure analogous to theprocedure described in 6-(3-nitrophenyl)-2-(4-phenoxyphenyl)nicotinamide(see Scheme 1) as brown gum (0.157 g, 41%). MS (ESI): m/z=381.1 [M+H]⁺.

Example 286-(4-acryloylpiperazin-1-yl)-2-(4-(cyclohexyloxy)phenyl)nicotinamide

The title compound was obtained using a procedure analogous to theprocedure described in Example 1 as white solid (61 mg, 34%). ¹H NMR(400 MHz, CD₃OD) δ 7.76 (d, J=8.7 Hz, 1H), 7.63 (d, J=8.7 Hz, 2H), 6.96(d, J=8.7 Hz, 2H), 6.87-6.76 (m, 2H), 6.27 (dd, J=16.8, 1.8 Hz, 1H),5.80 (dd, J=10.6, 1.8 Hz, 1H), 4.43-4.35 (m, 1H), 3.79-3.75 (m, 8H),2.07-1.96 (m, 2H), 1.89-1.78 (m, 2H), 1.63-1.34 (m, 6H). MS (ESI, methodA): m/z=435.2 [M+H]⁺, t_(R)=1.800 (min). HPLC: 98.2% (214 nm), 98.5%(254 nm).

2-(3-methoxy-4-methylphenyl)-6-(piperazin-1-yl)nicotinamide (3)

The title compound was obtained using a procedure analogous to theprocedure described in2-(4-(hydroxy(phenyl)methyl)phenyl)-6-(piperidin-4-yl)nicotinamide (seeScheme 48) as brown solid (0.238 g, 58%). MS (ESI): m/z=327.1 [M+H]⁺.

Example 296-(4-acryloylpiperazin-1-yl)-2-(3-methoxy-4-methylphenyl)nicotinamide

The title compound was obtained using a procedure analogous to theprocedure described in Example 1 as white solid (115 mg, 43%). ¹H NMR(400 MHz, CDCl₃) δ 7.77 (d, J=8.7 Hz, 1H), 7.23 (s, 1H), 7.21-7.15 (m,2H), 6.88-6.78 (m, 2H), 6.26 (dd, J=16.8, 1.9 Hz, 1H), 5.80 (dd, J=10.6,1.9 Hz, 1H), 3.88 (s, 3H), 3.75-3.78 (m, 8H), 2.24 (s, 3H). MS (ESLmethod A): m/z=381.1 [M+H]⁺, t_(R)=1.513 (min). HPLC: 95.9% (214 nm),98.7% (254 nm).

2-(4-fluoro-3-methoxyphenyl)-6-(piperazin-1-yl)nicotinamide (3)

The title compound was obtained using a procedure analogous to theprocedure described in 6-(3-nitrophenyl)-2-(4-phenoxyphenyl)nicotinamide(see Scheme 1) as brown gum (0.264 g, 72%). MS (ESI): m/z=331.1 [M+H]⁺.

Example 306-(4-acryloylpiperazin-1-yl)-2-(4-fluoro-3-methoxyphenyl)nicotinamide

The title compound was obtained using a procedure analogous to theprocedure described in Example 1 as white solid (45 mg, 15%). ¹H NMR(400 MHz, CD₃OD) δ 7.78 (d, J=8.7 Hz, 1H), 7.41 (dd, J=8.3, 2.0 Hz, 1H),7.28-7.22 (m, 1H), 7.16-7.12 (m, =1H), 6.88-6.77 (m, 2H), 6.27 (dd,J=16.8, 1.9 Hz, 1H), 5.80 (dd, J=10.6, 1.9 Hz, 1H), 3.93 (s, 3H),3.87-3.71 (m, 8H). MS (ESI, method A): m/z=385.1 [M+H]⁺, t_(R)=1.527(min). HPLC: 99.6% (214 nm), 99.7% (254 nm).

5-bromo-2-phenoxypyridine (3)

The title compound was obtained using a procedure analogous to theprocedure described in 4-(4-bromophenoxy)benzonitrile (see Scheme 16) asyellow solid (3.85 g, 81%).

2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4)

The title compound was obtained using a procedure analogous to theprocedure described in4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile(see Scheme 16) as yellow solid (0.536 g, 90%).

6′-phenoxy-6-(piperazin-1-yl)-2,3′-bipyridine-3-carboxamide (6)

The title compound was obtained using a procedure analogous to theprocedure described in 6-(3-nitrophenyl)-2-(4-phenoxyphenyl)nicotinamide(see Scheme 1) as brown gum (0.14 g, 55%). MS (ESI): m/z=376.1 [M+H]⁺.

Example 316-(4-acryloylpiperazin-1-yl)-6′-phenoxy-2,3′-bipyridine-3-carboxamide

The title compound was obtained using a procedure analogous to theprocedure described in Example 1 as white solid (50 mg, 31%). ¹H NMR(400 MHz, CD₃OD) δ 8.43 (d, J=2.4 Hz, 1H), 8.10 (dd, J=8.6, 2.4 Hz, 1H),7.80 (d, J=8.7 Hz, 1H), 7.49-7.41 (m, 2H), 7.29-7.22 (m, 1H), 7.16 (d,J=7.9 Hz, 2H), 6.97 (d, J=8.6 Hz, 1H), 6.88-6.77 (m, 2H), 6.27 (dd,J=16.8, 1.8 Hz, 1H), 5.80 (dd, J=10.6, 1.8 Hz, 1H), 3.87-3.69 (m, 8H).MS (ESI, method A): m/z=430.1 [M+H]⁺, t_(R)=1.620 (min). HPLC: 95.1%(214 nm), 96.2% (254 nm).

2-(4-bromophenoxy)pyridine (3)

The title compound was obtained using a procedure analogous to theprocedure described in 4-(4-bromophenoxy)benzonitrile (see Scheme 16) asyellow solid (2.83 g, 57%). MS (ESI): m/z=250.1 [M+H]⁺.

2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine (4)

The title compound was obtained using a procedure analogous to theprocedure described in4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile(see Scheme 16) as brown solid (0.882 g, 74%). MS (ESI): m/z=298.1[M+H]⁺.

6-(piperazin-1-yl)-2-(4-(pyridin-2-yloxy)phenyl)nicotinamide (6)

The title compound was obtained using a procedure analogous to theprocedure described in2-(4-(hydroxy(phenyl)methyl)phenyl)-6-(piperidin-4-yl)nicotinamide (seeScheme 48) as brown gum (0.198 g, 53%). MS (ESI): m/z=376.0 [M+H]⁺.

Example 326-(4-acryloylpiperazin-1-yl)-2-(4-(pyridin-2-yloxy)phenyl)nicotinamide

The title compound was obtained using a procedure analogous to theprocedure described in Example 1 as white solid (41 mg, 18%). ¹H NMR(400 MHz, CD₃OD) δ 8.18 (dd, J=5.0, 1.4 Hz, 1H), 7.86 (ddd, J=8.4, 7.3,2.0 Hz, 1H), 7.82-7.74 (m, 3H), 7.20-7.14 (m, 3H), 7.01 (d, J=8.3 Hz,1H), 6.88-6.79 (m, 2H), 6.27 (dd, J=16.8, 1.9 Hz, 1H), 5.80 (dd, J=10.6,1.9 Hz, 1H), 3.86-3.71 (m, 8H). MS (ESI, method A): m/z=430.1 [M+H]⁺,t_(R)=1.560 (min). HPLC: 100% (214 nm), 100% (254 nm).

2-(4-chlorophenyl)-6-(piperazin-1-yl)nicotinamide (3)

The title compound was obtained using a procedure analogous to theprocedure described in2-(4-(hydroxy(phenyl)methyl)phenyl)-6-(piperidin-4-yl)nicotinamide (seeScheme 48) as brown gum (0.23 g, 72%).

Example 33 6-(4-acryloylpiperazin-1-yl)-2-(4-chlorophenyl)nicotinamide

The title compound was obtained using a procedure analogous to theprocedure described in Example 1 as white solid (50 mg, 18%). ¹H NMR(400 MHz, CD₃OD) δ 7.78 (d, J=8.7 Hz, 1H), 7.72-7.64 (m, 2H), 7.45-7.39(m, 2H), 6.88-6.76 (m, 2H), 6.27 (dd, J=16.8, 1.9 Hz, 1H), 5.80 (dd,J=10.6, 1.9 Hz, 1H), 3.87-3.69 (m, 8H). MS (ESI, method A): m/z=371.0[M+H]⁺, t_(R)=1.645 (min). HPLC: 95.1% (214 nm), 95.3% (254 nm).

Ethyl 3-oxo-3-(4-phenoxyphenyl)propanoate (2)

To a solution of diethyl carbonate (14 g, 120 mmol) in toluene (100 mL)was added NaH (60%, 4.7 g, 12 mmol) at 0° C., and the resulting solutionwas heated to 90° C., then a solution of 1-(4-phenoxyphenyl)ethanone 1(10 g, 47 mmol) in toluene (50 mL) was added drop-wise over 30 min, andthe solution was refluxed for 20 min. After cooling to room temperature,AcOH/H₂O (55 mL/275 mL) was added. Toluene was removed under vacuum, andthe crude residue was diluted with water (500 mL). Then the mixture wasextracted with dichloromethane (4×800 mL). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel columnchromatography eluting with 9:1 PE/EA to get the title compound as brownoil (11.5 g, 79%). MS (ESI): m/z=285.0 [M+H]⁺.

Ethyl 3-(dimethylamino)-2-(4-phenoxybenzoyl)acrylate (3)

A solution of ethyl 3-oxo-3-(4-phenoxyphenyl)propanoate 2 (9.6 g, 34mmol) in DMA-DMF (100 mL) was stirred at 100° C. for 1 h. The resultingsolution was concentrated in high vacuum to get the title compound (12g, 100%) as brown thick oil. MS (ESI): m/z=340.1 [M+H]⁺.

Ethyl 3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate (4)

To a solution of ethyl 3-(dimethylamino)-2-(4-phenoxybenzoyl)acrylate 3(6 g, 17 mmol) in ethanol (30 mL) was added hydrazine hydrate (875 mg,17 mmol), and the resulting solution was heated to 85° C. and stirredfor 3 h. The solvent was evaporated and the crude residue was purifiedby silica gel column chromatography eluting with 4:1 PE/EA to get thetitle compound as brown oil (4.3 g, 78%). MS (ESI): m/z=309.0 [M+H]⁺.

Ethyl-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4carboxylate (6c)

Cs₂CO₃ (1.08 g, 3.3 mmol) was added to a solution of ethyl3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate 4 (500 mg, 1.6 mmol) andtert-butyl 3-(tosyloxy)pyrrolidine-1-carboxylate 5c (1.1 g, 3.2 mmol) inDMF (20 mL) and the resulting mixture was stirred at 100° C. for 16 h.The reaction mixture was concentrated in high vacuum and the cruderesidue was purified by silica gel column chromatography eluting with20:1 DCM/EA to get the title compound (780 mg, 100%) as colorless thickoil. MS (ESI): m/z=478.1 [M+H]⁺.

Similar procedures were used to prepare the following compounds: 6a, 6b,6d, 6g, 6h.

tert-butyl-3-(4-(ethoxycarbonyl)-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(6a)

thick colorless oil, 340 mg, 36%. MS (ESI): m/z=492.1 [M+H]⁺.

tert-butyl-4-(4-(ethoxycarbonyl)-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(6b)

thick oil, 557 mg, 71%. MS (ESI): m/z=492.1 [M+H]⁺.

Ethyl-1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate(6d)

white solid, 1.7 g, 61%. MS (ESI): m/z=464.1 [M+H]⁺.

(S)-ethyl-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate(6g)

colorless oil, 1.5 g, 99%. MS (ESI): m/z=478.1 [M+H]⁺.

(R)-ethyl-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate(6h)

yellow oil, 2 g, 100%. MS (ESI): m/z=478.1 [M+H]⁺.

Ethyl 1-(4-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate(6e)

To a solution of ethyl 3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate 4(300 mg, 1.0 mmol) and 1-fluoro-4-nitrobenzene 5e (140 mg, 1.0 mmol) in1-methyl-2-pyrrolidone (8 mL) was added cesium carbonate (950 mg, 3.0mmol), and the resulting solution was heated to 130° C. and stirred for3 h. After cooling to ambient temperature, the solvent was evaporatedand the crude residue was purified by silica gel column chromatographyeluting with 4:1 PE/EA to get the title compound as a yellow solid (290mg, 68%). MS (ESI): m/z=430.1 [M+H]⁺.

Similar procedures were used to prepare compound of 6f:

ethyl 1-(3-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate(6f)

yellow solid, 290 mg, 40%. MS (ESI): m/z=430.1 [M+H]⁺.

1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylicacid (7c)

To a solution of ethyl1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate6c (390 mg, 0.8 mmol) in EtOH (8 mL) was added IN LiOH/H₂O (4 mL). thereaction mixture was stirred at 75° C. for 1 h. Then to the solution wasadded IN HCl/H₂O to pH=4-5, concentrated to give title compound (690 mg,crude) as white solid contented LiCl salt. MS (ESI): m/z=450.1 [M+H]⁺.

Similar procedures were used to prepare the following compounds: 7a, 7b,7d, 7e, 7f, 7g, 7h.

1-(1-(tert-butoxycarbonyl)piperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylicacid (7a)

white solid, 310 mg, 100%. MS (ESI): m/z=464.1 [M+H]⁺.

1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylicacid (7b)

yellow solid, 525 mg, 99%. MS (ESI): m/z=464.1 [M+H]⁺.

1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylicacid (7d)

yellow solid, 300 mg, 80%. MS (ESI): m/z=436.1 [M+H]⁺.

1-(4-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylic acid (7e)

white solid, 280 mg, 99%. MS (ESI): m/z=402.1 [M+H]⁺.

1-(3-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylic acid (7f)

yellow oil, 260 mg, 100%. MS (ESI): mm/z=402.1 [M+H]⁺.

(S)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylicacid (7g)

yellow foam, 1.2 g, 99%. MS (ESI): m z=450.1 [M+H]⁺.

(R)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylicacid (7h)

yellow oil, 1.2 g, 99%. MS (ESI): m/z=450.1 [M+H]⁺.

Tert-butyl-3-(4-carbamoyl-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate(8c)

To a solution of1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylicacid 7c (630 mg, crude, 0.67 mmol) in DMF (20 mL) was added HATU (510mg, 1.33 mmol) and stirred at rt for 30 minutes, the resulting solutionwas bubbled with NH₃ gas for 10 minutes. After stirring at rt for 1 h,the solution was concentrated in high vacuum and the crude residue wasdiluted with DCM (50 mL), washed with water (3×20 mL), dried overNa₂SO₄, concentrated to give a residue which was purified by silica gelcolumn chromatography eluting with 100:1 DCM/MeOH to get the titlecompound (120 mg, 33%) as colorless foam. MS (ESI): m/z=471.2 [M+Na]⁺.

Similar procedures were used to prepare the following compounds: Sa, 8b,8d, 8e, 8f, 8g, 8h

tert-butyl-3-(4-carbamoyl-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(8a)

colorless oil, 310 mg, 100%. MS (ESI): m/z=463.1 [M+H]⁺.

tert-butyl-4-(4-carbamoyl-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(8b)

yellow solid, 320 mg, 63%. MS (ESI): m/z=463.1 [M+H]⁺.

tert-butyl-3-(4-carbamoyl-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(8d)

yellow solid, 300 mg, 99%. MS (ESI): m/z=435.1 [M+H]⁺.

1-(4-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (8e)

yellow solid, 230 mg, 99%. MS (ESI): m/z=401.1 [M+H]⁺.

1-(3-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (8f)

yellow solid, 260 mg, 100%. MS (ESI): m/z=401.0 [M+H]⁺.

(S)-tert-butyl-3-(4-carbamoyl-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate(8g)

white solid, 1.2 g, 100%. MS (ESI): m/z=449.0 [M+H]⁺.

(R)-tert-butyl-3-(4-carbamoyl-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate(8h)

white solid, 960 mg, 80%. MS (ESI): m/z=449.0 [M+H]⁺.

3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide

To a solution of tert-butyl3-(4-carbamoyl-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate8c (120 mg, 0.27 mmol) in DCM (10 mL) was added 6 N HCl/EtOH (5 mL, 30mmol), stirred at rt for 1 h, the resulting solution was concentrated inhigh vacuum and the crude residue was purified by Prep-HPLC to givetitle compound (86 mg, 91%) as white solid. ¹H NMR (400 MHz, CD₃OD): δ8.20 (s, 1H), 7.75 (d, J=8.6 Hz, 2H), 7.43-7.36 (m, 2H), 7.20-7.13 (m,1H), 7.08-7.00 (m, 4H), 5.32-5.27 (m, 1H), 3.87-3.72 (m, 3H), 3.59-3.50(m, 1H), 2.67-2.56 (m, 1H), 2.52-2.43 (m, 1H). MS (ESI, Method A):m/z=349.1 [M+H]⁺, t_(R)=1.242 min. HPLC: 99.3% (214 nm), 99.5% (254 nm).

Similar procedures were used to prepare the following compounds: 9a, 9b,9d, 9g, 9e, and 9f.

3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide (9a)

white solid, 240 mg, 99%0. ¹H NMR (400 MHz, CD₃OD): δ 8.23 (s, 1H), 7.73(d, J=8.6 Hz, 2H), 7.48-7.31 (m, 2H), 7.21-7.12 (m, 1H), 7.12-6.97 (m,4H), 4.76-4.65 (m, 1H), 3.74-3.57 (m, 2H), 3.43-3.36 (m, 1H), 3.28-3.15(m, 1H), 2.39-2.02 (m, 3H), 2.01-1.84 (m, 1H). MS (ESI, Method A):m/z=363.2 [M+H]¹, t_(R)=1.255 min. HPLC: 100% (214 nm), 100% (254 nm).

3-(4-phenoxyphenyl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide (9b)

light yellow solid, 3.1 mg, 40%. ¹H NMR (300 MHz, CD₃OD): δ 8.18 (s,1H), 7.67 (d, J=8.7 Hz, 2H), 7.43-7.31 (m, 2H), 7.19-7.09 (m, 1H),7.07-6.95 (m, 4H), 4.65-4.55 (m, 1H), 3.64-3.54 (m, 2H), 3.29-3.17 (m,2H), 2.42-2.23 (m, 4H). MS (ESI, Method A): m/z=363.0 [M+H]⁺,t_(R)=1.288 min. HPLC: 100% (214 nm), 100% (254 nm).

1-(azetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (Example14) (9d)

yellow solid, 300 mg, 100%. ¹H NMR (300 MHz, CD₃OD): δ 8.20-8.14 (m,1H), 7.82-7.66 (m, 2H), 7.44-7.30 (m, 2H), 7.18-7.11 (m, 1H), 7.07-6.96(m, 4H), 5.52-5.40 (m, 1H), 4.64-4.55 (m, 4H). MS (ESI, Method A):m/z=335.1 [M+H]⁺, t_(R)=1.235-1.255 min. HPLC: 100% (214 nm), 100% (254nm).

(S)-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide(9g)

white solid, 90 mg, 83%. ¹H NMR (400 MHz, CD₃OD): δ 8.25 (s, 1H),7.80-7.68 (m, 2H), 7.45-7.33 (m, 2H), 7.20-7.11 (m, 1H), 7.11-6.98 (m,4H), 5.38-5.25 (m, 1H), 3.88-3.69 (m, 3H), 3.62-3.49 (m, 1H), 2.68-2.54(m, 1H), 2.54-2.40 (m, 1H). MS (ESI, Method A): m/z=349.1 [M+H]⁺,t_(R)=1.219 min. HPLC: 100% (214 nm), 100% (254 nm).

(R)-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide(9h)

yellow oil, 100 mg, 100%. MS (ESI, Method A): m/z=349.1 [M+H]⁺.

1-(4-aminophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (9e)

To a solution of1-(4-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide 8e (200mg, 0.50 mmol) in ethanol (8 mL) was added saturated aqueous NH₄Cl (4mL), followed by the addition of zinc powder (260 mg, 4.0 mmol) inportion over 5 min, then the resulting solution was stirred for 10 h atambient temperature. The mixture was filtered and the filtrate wasdiluted with ethyl acetate (30 mL), and washed with water (2×20 mL) andbrine (2×20 mL). The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated to give the title compound as ayellow solid (150 mg, 81%). ¹H NMR (400 MHz, CD₃OD): δ 8.47 (s, 1H),7.78 (d, J=8.7 Hz, 2H), 7.51 (d, J=8.7 Hz, 2H), 7.44-7.36 (m, 2H), 7.16(s, 1H), 7.19-7.13 (m, 4H), 6.83 (d, J=8.7 Hz, 2H). MS (ESI, Method A):m/z=371.1 [M+H]⁺, t_(R)=1.468 min. HPLC: 97.8% (214 nm), 98.0% (254 nm).

Similar procedures were used to prepare compound 8f.

1-(3-aminophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (8f)

white solid, 105 mg, 47%. ¹H NMR (400 MHz, CD₃OD): δ 8.60 (s, 1H), 7.81(d, J=8.6 Hz, 2H), 7.44-7.36 (m, 2H), 7.28-7.03 (m, 8H), 6.75 (d, I=7.9Hz, 1H). MS (ESI, Method A): m/z=371.1 [M+H]⁺, t_(R)=1.507 min. HPLC:96.9% (214 nm), 98.2% (254 nm).

1-(1-acryloylpyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide(Example 13) (10c)

To a solution of3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide 9c (43mg, 0.12 mmol) and TEA (50 mg, 0.5 mmol) in DCM (10 mL) was addedacryloyl chloride (22 mg, 0.24 mmol) and stirred at 75° C. for 1 h, theresulting was concentrated and purified by Prep-TLC eluting with 10:1DCM/MeOH to get the title compound (17 mg, 35%) as white solid. ¹H NMR(400 MHz, CD₃OD): δ 8.18 (d, J=8.7 Hz, 1H), 7.70 (d, J=8.6 Hz, 2H),7.43-7.34 (m, 2H), 7.18-7.08 (m, 1H), 7.03 (dd, J=15.5, 8.3 Hz, 4H),6.72-6.58 (m, 1H), 6.32 (dd, J=15.9, 4.0 Hz, 1H), 5.83-5.73 (m, 1H),5.18-5.04 (m, 1H), 4.21-3.65 (m, 4H), 2.63-2.45 (m, 2H). MS (ESI, MethodA): m/z=403.1 [M+H]⁺, t_(R)=1.414 min. HPLC: 95.3% (214 nm), 95.3% (254nm).

Similar procedures were used to prepare the following compounds: 10a,10b, 10d, 10e, 10f, 10g and 10h.

1-(1-acryloylpiperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide(Example 11) (10a)

White solid, 39 mg, 23%. ¹H NMR (400 MHz, CD₃OD) δ 8.20 (d, J=5.4 Hz,1H), 7.71 (d, J=8.3 Hz, 2H), 7.44-7.35 (m, 2H), 7.19-7.12 (m, 1H), 7.04(dd, J=12.3, 8.4 Hz, 4H), 6.89-6.73 (m, 1H), 6.3-6.12 (m, 1H), 5.76 (dd,J=25.5, 10.7 Hz, 1H), 4.71 (d, J=11.5 Hz, 0.5H), 4.45-4.17 (m, 2H), 4.08(d, J=14.3 Hz, 0.5H), 3.85-3.73 (m, 0.5H), 3.45-3.34 (m, 1H), 3.27-3.14(m, 0.5H), 2.39-2.18 (m, 2H), 2.06-1.92 (m, 1H), 1.71-1.61 (m, 1H). MS(ESI, Method A): m/z=417.2 [M+H]⁺, t_(R)=1.468 min. HPLC: 97.7% (214nm), 98.7% (254 nm).

1-(1-acryloylpiperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide(Example 12) (10b)

White solid, 4.7 mg, 20.8%. ¹H NMR (400 MHz, CD₃OD) δ 8.19 (s, 1H), 7.69(d, J=8.5 Hz, 2H), 7.45-7.33 (m, 2H), 7.25-7.12 (m, 1H), 7.04 (dd,J=12.2, 8.5 Hz, 4H), 6.84 (dd, J=16.8, 10.7 Hz, 1H), 6.24 (dd, J=16.8,1.5 Hz, 1H), 5.79 (dd, J=10.7, 1.5 Hz, 1H), 4.77-4.64 (m, 1H), 4.61-4.46(m, 1H), 4.35-4.23 (m, 1H), 3.38 (d, J=13.0 Hz, 1H), 3.03-2.92 (m, 1H),2.34-2.17 (m, 2H), 2.12-1.96 (m, 2H). MS (ESI, Method A): m/z=417.1[M+H]¹, t_(R)=1.421 min. HPLC: 97.5% (214 nm), 97.8% (254 nm).

1-(1-acryloylazetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide(10d)

White solid, 19 mg, 18%. ¹H NMR (300 MHz, CD₃OD) δ 8.21 (s, 1H), 7.71(d, J=9.1 Hz, 2H), 7.42-7.31 (m, 2H), 7.20-7.09 (m, 1H), 7.06-6.94 (m,4H), 6.46-6.22 (m, 2H), 5.78 (dd, J=9.9, 2.3 Hz, 1H), 5.33 (td, J=8.0,4.0 Hz, 1H), 4.83-4.65 (m, 2H), 4.62-4.41 (m, 2H). MS (ESI, Method A):m/z=389.1 [M+H]⁺, t_(R)=1.388-1.401 min. HPLC: 95.1% (214 nm), 96.1%(254 nm).

1-(4-acrylamidophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide(Example 16) (10e)

White solid, 52 mg, 46%. ¹H NMR (400 MHz, CD₃OD) δ 8.67 (s, 1H),7.89-7.78 (m, 6H), 7.44-7.36 (m, 2H), 7.20-7.12 (m, 1H), 7.11-7.02 (m,4H), 6.52-6.37 (m, 2H), 5.82 (dd, J=9.4, 2.4 Hz, 1H). MS (ESI, MethodA): m/z=425.2 [M+H]¹, t_(R)=1.521 min. HPLC: 97.3% (214 nm), 97.0% (254nm).

1-(3-acrylamidophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide(Example 18) (10f)

White solid, 24 mg, 24° %. ¹H NMR (400 MHz, CD₃OD) δ 8.70 (s, 1H), 8.35(s, 1H), 7.84 (d, J=8.7 Hz, 2H), 7.60 (d, J=8.1 Hz, 2H), 7.54-7.48 (m,1H), 7.44-7.36 (m, 2H), 7.11-7.03 (m, 1H), 7.20-7.13 (m, 4H), 6.53-6.38(m, 2H), 5.83 (dd, J=9.2, 2.6 Hz, 1H). MS (ESI, Method A): m/z=425.1[M+H]⁺, t_(R)=1.547 (min). HPLC: 97.6% (214 nm), 98.6% (254 nm).

(S)-1-(1-acryloylpyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide(Example 20) (10g)

Gray solid, 120 mg, 27%. ¹H NMR (400 MHz, CD₃OD): δ 8.21 (d, J=6.6 Hz,1H), 7.73-7.64 (m, 2H), 7.43-7.34 (m, 2H), 7.20-7.10 (m, 1H), 7.10-6.96(m, 4H), 6.75-6.55 (m, 1H), 6.32 (ddd, J=16.8, 4.8, 1.9 Hz, 1H),5.86-5.72 (m, 1H), 5.21-5.03 (m, 1H), 4.22-4.07 (m, 1H), 4.05-3.67 (m,3H), 2.64-2.43 (m, 2H). MS (ESI, Method A): m/z=403.2 [M+H]¹,t_(R)=1.421 min. HPLC: 99.0% (214 nm), 99.0% (254 nm).

(R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide(Example 19) (10h)

White solid, 20 mg, 6%. ¹H NMR (300 MHz, CD₃OD): δ 8.16 (d, J=5.9 Hz,1H), 7.67 (d, J=8.7 Hz, 2H), 7.42-7.30 (m, 2H), 7.17-6.92 (m, 5H),6.71-6.56 (m, 1H), 6.34-6.25 (m, 1H), 5.80-5.72 (m, 1H), 5.18-5.02 (m,1H), 4.20-4.05 (m, 1H), 4.02-3.65 (m, 3H), 2.62-2.45 (m, 2H). MS (ESI,Method A): m/z=403.1 [M+H]⁺, t_(R)=1.409 min. HPLC: 95.0% (214 nm),97.0% (254 nm).

Example 341-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide

To a solution of 4-(dimethylamino)but-2-enoic acid 11 (22 mg, 0.17 mmol)and HATU (98 mg, 0.26 mmol) in DMF (10 mL) was added3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide 9c(Scheme 23) (60 mg, 0.17 mmol) and DIPEA (22 mg, 0.5 mmol). The reactionmixture was stirred at rt for 1 h. The solution was concentrated in highvacuum and the residue was diluted in DCM (10 mL), washed with water(3×10 mL), dried over Na₂SO₄, concentrated to give a residue which waspurified by Prep-TLC eluting with 10:1 DCM/MeOH to get the titlecompound (26 mg, 37%) as brown solid. ¹H NMR (300 MHz, CD₃OD): δ 8.20(d, J=9.0 Hz, 1H), 7.73-7.56 (m, 2H), 7.41-7.27 (m, 2H), 7.11 (t, J=7.4Hz, 1H), 7.05-6.91 (m, 4H), 6.88-6.66 (m, 2H), 5.22-5.02 (m, 1H),4.24-4.06 (m, 1H), 4.05-3.76 (m, 4.5H), 3.76-3.61 (m, 0.5H), 2.86 (d,J=6.1 Hz, 6H), 2.66-2.39 (m, 2H). MS (ESL Method A): m/z=459.8 [M+H]⁺,t_(R)=1.244 min. HPLC: 97.5% (214 nm), 98.2% (254 nm).

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2)

The title compound was obtained using a procedure analogous to theprocedure described in4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile(see Scheme 16) as white solid (10.2 g, 80%).

2-(4-(3-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(4)

The mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol 2(1.0 g, 4.5 mmol), 3-fluorophenylboronic acid 3 (0.70 g, 5.0 mmol),Cu(OAc)₂ (1.0 g, 5.0 mmol), Et₃N (2.75 g, 27.3 mmol), 4A molecularsieves (1 g) and CH₂Cl₂ (15 mL) was stirred at rt for 16 h. Then themixture was concentrated in vacuo and the residue was purified by silicagel chromatography eluting with 20:1 petroleum ether/EtOAc to afford thetitle compound (0.45 g, 32%) as white solid.

2-(4-(3-fluorophenoxy)phenyl)-6-(piperazin-1-yl)nicotinamide (6)

The title compound was obtained using a procedure analogous to theprocedure described in 6-(3-nitrophenyl)-2-(4-phenoxyphenyl)nicotinamide(see Scheme 1) as white solid (0.15 g, 41%). MS (ESI): m/z=393.1 [M+H]⁺.

Example 356-(4-acryloylpiperazin-1-yl)-2-(4-(3-fluorophenoxy)phenyl)nicotinamide

The title compound was obtained using a procedure analogous to theprocedure described in Example 1 as white solid (50 mg, 27%). ¹H NMR(400 MHz, CD₃OD) δ 7.79 (d, J=8.7 Hz, 1H), 7.77-7.70 (m, 2H), 7.42-7.33(m, 1H), 7.13-7.06 (m, 2H), 6.93-6.75 (m, 5H), 6.27 (dd, J=16.8, 1.9 Hz,1H), 5.80 (dd, J=10.6, 1.9 Hz, 1H), 3.84-3.72 (m, 8H). MS (ESI, methodA): m/z=447.1 [M+H], t_(R)=1.746 (min). HPLC: 95.9% (214 nm), 96.4% (254nm).

4-bromo-2-fluoro-1-phenoxybenzene (3)

The title compound was obtained using a procedure analogous to theprocedure described in2-(4-(3-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(see Scheme 25) as yellow oil (1.5 g, 21%). MS (ESI): m/z=267.1 [M+H]⁺.

2-(3-fluoro-4-phenoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5)

The title compound was obtained using a procedure analogous to theprocedure described in4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile(see Scheme 16) as yellow oil (1.04 g, 73%).

2-(3-fluoro-4-phenoxyphenyl)-6-(piperazin-1-yl)nicotinamide (7)

The title compound was obtained using a procedure analogous to theprocedure described in 6-(3-nitrophenyl)-2-(4-phenoxyphenyl)nicotinamide(see Scheme 1) as brown gum (0.194 g, 49%). MS (ESI): m/z=393.1 [M+H]⁺.

Example 366-(4-acryloylpiperazin-1-yl)-2-(3-fluoro-4-phenoxyphenyl)nicotinamide

The title compound was obtained using a procedure analogous to theprocedure described in Example 1 as white solid (38 mg, 17%). ¹H NMR(400 MHz, DMSO-d6) 5 (m, 2H), 7.59 (d, J=11.4 Hz, 1H), 7.48 (d, J=8.2Hz, 1H), 7.42 (t, J=7.7 Hz, 2H), 7.35-7.28 (m, 1H), 7.24-7.15 (m, 2H),7.04 (d, J=7.9 Hz, 2H), 6.95-6.81 (m, 2H), 6.16 (d, J=16.6 Hz, 1H), 5.73(d, J=10.2 Hz, 1H), 3.79-3.50 (m, 8H). MS (ESI, method A): m/z=447.1[M+H]⁺, t_(R)=1.753 (min). HPLC: 98.6% (214 nm), 98.4% (254 nm).

2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(3)

The title compound was obtained using a procedure analogous to theprocedure described in2-(4-(3-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(see Scheme 25) as white solid (0.45 g, 32%).

2-(4-(4-fluorophenoxy)phenyl)-6-(piperazin-1-yl)nicotinamide (5)

The title compound was obtained using a procedure analogous to theprocedure described in 6-(3-nitrophenyl)-2-(4-phenoxyphenyl)nicotinamide(see Scheme 1) as brown gum (0.18 g, 41%).

Example 376-(4-acryloylpiperazin-1-yl)-2-(4-(4-fluorophenoxy)phenyl)nicotinamide

The title compound was obtained using a procedure analogous to theprocedure described in Example 1 as white solid (80 mg, 44%). ¹H NMR(400 MHz, CD₃OD) δ 7.77 (d, J=8.7 Hz, 1H), 7.69 (d, J=8.7 Hz, 2H),7.17-7.05 (m, 4H), 7.00 (d, J=8.7 Hz, 2H), 6.87-6.76 (m, 2H), 6.26 (dd,J=16.8, 1.8 Hz, 1H), 5.80 (dd, J=10.6, 1.8 Hz, 1H), 3.87-3.71 (m, 8H).MS (ESI, method A): m/z=447.0 [M+H]¹, t_(R)=1.739 (min). HPLC: 99.8%(214 nm), 100% (254 nm).

1-fluoro-2-(4-nitrophenoxy)benzene (3)

The mixture of 1-fluoro-4-nitrobenzene 1 (10.0 g, 70.8 mmol),2-fluorophenol 2 (9.54 g, 85.0 mmol), Cs₂CO₃ (34.6 g, 106 mmol) and DMF(80 mL) was heated to 120° C. and stirred for 2 h. After being cooled tort, the mixture was diluted with water (150 mL) and extracted with EtOAc(200 mL×2). The combined organic phase was washed with brine (100 mL×3),dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuo.The residue was recrystallized from MeOH (20 mL×2) to afford the titlecompound as light yellow solid (14.6 g, 88%).

4-(2-fluorophenoxy)benzenamine (4)

To the mixture of 1-fluoro-2-(4-nitrophenoxy)benzene 3 (16.2 g, 69.3mmol), saturated aqueous NH₄Cl solution (30 mL) and EtOH (150 mL) wasadded iron powder (19.4 g, 347 mmol) slowly and then the resultingmixture was heated to 70° C. for 3.5 h. After being cooled to rt, themixture was filtered. The filtrate was concentrated in vacuo. Theresidue was dissolved in EtOAc (160 mL) and washed successively withwater (100 mL×2) and brine (100 mL×2). The organic phase was dried overNa₂SO₄, filtered and concentrated in vacuo to afford the title compound(13.6 g, 96%) as yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 7.35-7.28 (m,1H), 7.14-7.00 (m, 2H), 6.93-6.85 (m, 1H), 6.80-6.73 (m, 2H), 6.64-6.56(m, 2H), 4.99 (brs, 2H).

1-fluoro-2-(4-iodophenoxy)benzene (5)

The mixture of 4-(2-fluorophenoxy)benzenamine 4 (7.94 g, 39.1 mmol),CH₂12 (29.0 g, 136.8 mmol) and CH₃CN (120 mL) was heated to 55° C. andthen amyl nitrite (11.6 g, 97.7 mmol) was added. The resulting mixturewas heated to 75° C. for 3.5 h. After being cooled to rt, the mixturewas diluted with EtOAc and then washed successively with 10% Na₂S₂O₃ andbrine. The organic phase was dried over Na₂SO₄, filtered, concentratedin vacuo and purified by silica gel chromatography eluting withpetroleum ether to afford the title compound (4.12 g, 51%) as lightyellow oil. ¹H NMR (400 MHz, DMSO) δ 7.78-7.63 (m, 2H), 7.44-7.37 (m,1H), 7.34-7.14 (m, 3H), 6.87-6.74 (m, 2H).

2-(4-(2-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(7)

The title compound was obtained using a procedure analogous to theprocedure described in4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile(see Scheme 16) as yellow oil (0.40 g, 13%).

2-(4-(2-fluorophenoxy)phenyl)-6-(piperazin-1-yl)nicotinamide (9)

The title compound was obtained using a procedure analogous to theprocedure described in 6-(3-nitrophenyl)-2-(4-phenoxyphenyl)nicotinamide(see Scheme 1) as white solid (0.16 g, 31%). MS (ESI): m/z=393.1 [M+H]⁺.

Example 386-(4-acryloylpiperazin-1-yl-2-(4-(2-fluorophenoxy)phenyl)nicotinamide

The title compound was obtained using a procedure analogous to theprocedure described in Example 1 as white solid (28 mg, 24%). ¹H NMR(400 MHz, CD₃OD) δ 7.77 (d, J=8.7 Hz, 1H), 7.71-7.68 (m, 2H), 7.34-7.13(m, 4H), 6.99 (d, J=8.7 Hz, 2H), 6.88-6.79 (m, 2H), 6.26 (dd, J=16.8,1.9 Hz, 1H), 5.80 (dd, J=10.6, 1.9 Hz, 1H), 3.89-3.71 (m, 8H). MS (ESI,method A): m/z=447.1 [M+H]⁺, t_(R)=1.723 (min). HPLC: 98.6% (214 nm),98.8% (254 nm).

3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2)

The title compound was obtained using a procedure analogous to theprocedure described in4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (see Scheme 25) aswhite solid (4.1 g, 66%). MS (ESI): m/z=239.2 [M+H]⁺.

2-(2-fluoro-4-phenoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4)

The title compound was obtained using a procedure analogous to theprocedure described in2-(4-(3-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(see Scheme 25) as white solid (2.1 g, 39%).

2-(2-fluoro-4-phenoxyphenyl)-6-(piperazin-1-yl)nicotinamide (6)

The title compound was obtained using a procedure analogous to theprocedure described in 6-(3-nitrophenyl)-2-(4-phenoxyphenyl)nicotinamide(see Scheme 1) as brown solid (0.105 g, 21%). MS (ESI): m/z=393.1[M+H]⁺.

Example 396-(4-acryloylpiperazin-1-yl)-2-(2-fluoro-4-phenoxyphenyl)nicotinamide

The title compound was obtained using a procedure analogous to theprocedure described in Example 1 as white solid (78 mg, 65%). ¹H NMR(400 MHz, MeOD) δ 7.78 (d, J=8.7 Hz, 1H), 7.59 (dd, J=11.8, 2.0 Hz, 1H),7.48 (d, J=9.2 Hz, 1H), 7.44-7.33 (m, 2H), 7.17-7.06 (m, 2H), 7.05-6.99(m, 2H), 6.90-6.79 (m, 2H), 6.27 (dd, J=16.8, 1.8 Hz, 1H), 5.80 (dd,J=10.6, 1.8 Hz, 1H), 3.86-3.70 (m, 8H). MS (ESI, method A): m/z=447.0[M+H]⁺, t_(R)=1.770 (min). HPLC: 96.5% (214 nm), 96.9% (254 nm).

tert-butyl 2-carbamoylpiperidine-1-carboxylate (2)

To a solution of 1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid 1(5.0 g, 21.8 mmol) in dry THF (100 mL) was added TEA (3.30 g, 32.7mmol), isobutyl carbonochloridate (3.27 g, 23.99 mmol) at 0° C. and theresulting solution was stirred for 20 min. NH₃—H₂O was added and stirredat rt for 2 h. The mixture was diluted with ethyl acetate (30 mL), andwashed with sat. aq. Na₂CO₃ (2×20 mL) and sat. aq. citric acid (2×20mL). The organic layer was dried over anhydrous sodium sulfate, filteredand concentrated to give crude product (3.6 g, 72%) as white solid. MS(ESI): m/z=173.0 [M−55]⁺.

tert-butyl 2-carbamothioylpiperidine-1-carboxylate (3)

To a solution of tert-butyl 2-carbamoylpiperidine-1-carboxylate 2 (2.0g, 8.77 mmol) in dry toluene (20 mL) was added Lawesson's reagent (2.13g, 5.26 mmol) at N₂ atmosphere. The resulting solution was stirred at80° C. for 16 h. The mixture was diluted with ethyl acetate (30 mL), andwashed with saturated aqueous (sat. aq.) Na₂CO₃ (2×20 mL) and brine(2×20 mL). The organic layer was dried over anhydrous sodium sulfate,filtered and concentrated to give crude product which was purified bysilica gel column chromatography eluting with 4:1 PE/EA to get the titlecompound (330 mg, 15%) as white solid. MS (ESI): m/z=245.2 [M+H]⁺.

ethyl-2-(1-(tert-butoxycarbonyl)piperidin-3-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxylate(5)

A solution of tert-butyl 2-carbamothioylpiperidine-1-carboxylate 3 (60mg, 0.239 mmol) and ethyl 2-bromo-3-oxo-3-(4-phenoxyphenyl)propanoate 4(250 mg, 0.7 mmol) in EtOH (10 mL) was stirred for 2 h at 60° C. Themixture was diluted with ethyl acetate (30 mL), and washed with water(2×20 mL) and brine (2×20 mL). The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated. The residue waspurified by silica gel column chromatography eluting with 40:1 PE/EA toget the title compound (120 mg, 34%) as colorless oil. MS (ESI):m/z=509.3[M+H]⁺.

2-(1-(tert-butoxycarbonyl)piperidin-3-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxylicacid (6)

A solution of ethyl2-(1-(tert-butoxycarbonyl)piperidin-3-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxylate5 (120 mg, 0.263 mmol) in THF-H₂O (1/1, 20 mL) and added LiOH (30 mg,0.71 mmol) was stirred at t for 13 h. The mixture was evaporated anddiluted with water (5 mL), and the solution was acidified with 2 Nhydrochloric acid to pH=4. The residue was extracted with Ethyl Acetate(EA) (3:30 mL). Dried and concentrated to get crude compound (110 mg,100%) as light red liquid. MS (ESI): m/z=481.0 [M+H]⁺.

tert-butyl3-(5-carbamoyl-4-(4-phenoxyphenyl)thiazol-2-yl)piperidine-1-carboxylate(7)

The mixture of2-(1-(tert-butoxycarbonyl)piperidin-3-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxylicacid 6 (110 mg, 0.229 mmol), HATU (113 mg, 0.297 mmol), DIPEA (88 mg,0.687 mmol) and dry DMF (10 mL) was bubbled with NH₃ for 20 min, and theresulting solution was stirred for 3 h at ambient temperature. Themixture was diluted with ethyl acetate (30 mL), and washed with water(2×20 mL) and brine (2×20 mL). The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated. The residue waspurified by Prep-TLC with 3:2 PE/EA to get the title compound (100 mg,75%) as colorless oil. MS (ESI): m/z=480.1 [M+H]⁺.

4-(4-phenoxyphenyl)-2-(piperidin-3-yl)thiazole-5-carboxamide (8)

To a solution of tert-butyl3-(5-carbamoyl-4-(4-phenoxyphenyl)thiazol-2-yl)piperidine-1-carboxylate7 (100 mg, 0.21 mmol) in DCM (5 mL) was added TFA (2.5 mL) at ambienttemperature. The mixture was stirred for 3 h. The mixture was dilutedwith water (2×150 mL) and extracted with ethyl acetate (2×20 mL) andwashed with brine (2×150 mL). The organic layer was dried over anhydroussodium sulfate, filtered and concentrated to give the title compound (60mg, 76%) as brown oil. MS (ESI): m % z=380.0 [M+H]⁺.

Example 402-(1-acryloylpiperidin-3-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxamide

To a solution of4-(4-phenoxyphenyl)-2-(piperidin-3-yl)thiazole-5-carboxamide 8 (60 mg,0.155 mmol) in dry dichloromethane (10 mL) were added TEA (19 mg, 0.21mmol) and acryloyl chloride 9 (32 mg, 0.316 mmol), and the resultingsolution was stirred at rt for 1 h. Water (10 mL) was added to quenchthe reaction. The mixture was diluted with ethyl acetate (30 mL), washedwith brine (2×20 mL). The organic layer was dried over Na₂SO₄, filteredand concentrated to get the residue which was purified by Prep-TLC with17:1 DCM/MeOH to get the title compound (33 mg, 50%) as a white solid.¹H NMR (400 MHz, DMSO) δ 7.76 (d, J=8.5 Hz, 2H), 7.76 (brs, 1H), 7.70(brs, 1H), 7.44 (t, J=8.0 Hz, 2H), 7.19 (t, J=7.4 Hz, 1H), 7.08 (t,J=8.6 Hz, 4H), 6.92-6.82 (m, 1H), 6.14-6.04 (m, 1H), 5.73-5.64 (m, 1H),4.65-4.62 (m, 0.5H), 4.15-4.04 (m, 0.5H), 4.02-4.00 (m, 1H), 3.59-3.56(m, 0.5H), 3.26-3.14 (m, 1.5H), 3.09-2.98 (m, 1H), 2.22-2.16 (m, 1H),1.90-1.74 (m, 2H), 1.58-1.48 (m, 1H). MS (ESI, method A): m/z=433.8[M+H], t_(R)=1.488 min. HPLC: 99.1% (214 nm), 99.2% (254 nm).

tert-butyl 3-carbamoylpyrrolidine-1-carboxylate (2)

To a solution of 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid 1(5 g, 23.23 mmol) in dry THF (100 mL) was added TEA (4.69 g, 46.46mmol), isobutyl carbonochloridate (3.8 g, 27.87 mmol) at 0° C. and theresulting solution was stirred for 20 min. NH₃—H₂O added and stirred atrt for 2 h. The mixture was diluted with ethyl acetate (30 mL), andwashed with saturated (sat.) Na₂CO₃ (2*20 mL) and sat. citric acid (2×20mL). The organic layer was dried over anhydrous sodium sulfate, filteredand concentrated to give crude product (2.39 g, 49%) as yellow solid. MS(ESI): m/z=159.0 [M+H]⁺.

tert-butyl 3-carbamothioylpyrrolidine-1-carboxylate (3)

To a solution of tert-butyl 3-carbamoylpyrrolidine-1-carboxylate 2 (0.76g, 3.55 mmol) in dry toluene (20 mL) was added Lawesson's regent (0.71g, 1.77 mmol) at N₂ atmosphere. The resulting solution was stirred at80° C. for 16 h. The mixture was diluted with ethyl acetate (30 mL), andwashed with sat. Na₂CO₃ (2×20 mL) and brine (2×20 mL). The organic layerwas dried over anhydrous sodium sulfate, filtered and concentrated togive crude product which was purified by silica gel columnchromatography eluting with 6:1 PE/EA to get the title compound (230 mg,28%) as brown oil. MS (ESI): m/z=175.2 [M+H]⁺.

ethyl2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxylate(5)

A solution of tert-butyl 3-carbamothioylpyrrolidine-1-carboxylate 3 (360mg, 0.1 mmol) and ethyl 2-bromo-3-oxo-3-(4-phenoxyphenyl)propanoate 4(230 mg, 0.1 mmol) in EtOH (10 mL) was stirred for 2 h at 60° C. Themixture was diluted with ethyl acetate (30 mL), and washed with water(2×20 mL) and brine (2×20 mL). The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated. The residue waspurified by silica gel column chromatography eluting with 30:1 PE/EA toget the title compound (100 mg, 20%) as colorless oil. MS (ESI):m/z=495.3[M+H]⁺.

2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxylicacid (6)

A solution of ethyl2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxylate5 (100 mg, 0.2 mmol) in THF-H₂O (1/1, 20 mL) and added LiOH (84 mg, 2mmol) was stirred at rt for 13 h. The mixture was evaporated and dilutedwith water (5 mL), and the solution was acidified with 2 N hydrochloricacid to pH=4. The residue was extracted with EA (3×30 mL). Dried andevaporated to get crude compound (95 mg, 100%) as red oil. MS (ESI):m/z=411.0 [M+H]⁺.

tert-butyl3-(5-carbamoyl-4-(4-phenoxyphenyl)thiazol-2-yl)pyrrolidine-1-carboxylate(7)

The mixture of2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxylicacid 6 (950 mg, 0.2 mmol), HATU (116 mg, 0.3 mmol), DIPEA (103 mg, 0.8mmol) and dry DMF (10 mL) was bubbled with NH₃ for 20 min, and theresulting solution was stirred for 3 h at ambient temperature. Themixture was diluted with ethyl acetate (30 mL), and washed with water(2×20 mL) and brine (2×20 mL). The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated. The residue waspurified by Prep-TLC with 2:1 PE/EA to get the title compound (70 mg,75%) as colorless oil. MS (ESI): m/z=466.1 [M+H]⁺.

tert-butyl3-(5-carbamoyl-4-(4-phenoxyphenyl)thiazol-2-yl)pyrrolidine-1-carboxylate(8)

To a solution of tert-butyl3-(5-carbamoyl-4-(4-phenoxyphenyl)thiazol-2-yl)pyrrolidine-1-carboxylate7 (70 mg, 0.15 mmol) in DCM (5 mL) was added TFA (2.5 mL) at ambienttemperature. The mixture was stirred for 3 h. The mixture was dilutedwith water (2×150 mL) and extracted with ethyl acetate (2×20 mL) andwashed with brine (2×150 mL). The organic layer was dried over anhydroussodium sulfate, filtered and concentrated to give the title compound (65mg, 100%) as brown oil. MS (ESI): m/z=366.1 [M+H]⁺.

Example 412-(1-acryloylpyrrolidin-3-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxamide

To a tert-butyl3-(5-carbamoyl-4-(4-phenoxyphenyl)thiazol-2-yl)pyrrolidine-1-carboxylate8 (65 mg, 0.15 mmol) in dry dichloromethane (10 mL) were added TEA (50mg, 0.45 mmol) and acryloyl chloride 9 (20.4 mg, 0.225 mmol), and theresulting solution was stirred at rt for 1 h. Water (10 mL) was added toquench the reaction. The mixture was diluted with ethyl acetate (30 mL),washed with brine (2×20 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated to get the residue which was purified byPrep-TLC with 1:1 PE/EA to get the title compound (22 mg, 35%) as awhite solid. ¹H NMR (400 MHz, DMSO) δ 7.76 (d, J=8.0 Hz, 2H), 7.76 (brs,1H), 7.70 (brs, 1H), 7.44 (t, J=8.0 Hz, 2H), 7.19 (t, J=7.4 Hz, 1H),7.07 (t, J=8.6 Hz, 4H), 6.65-6.59 (m, 1H), 6.19-6.15 (m, 1H), 5.72-5.68(m, 1H), 4.11-4.07 (m, 0.5H), 3.99-3.95 (m, 0.5H), 3.91-3.78 (m, 2H),3.70-3.62 (m, 1.5H), 3.50-3.47 (m, 0.5H), 2.44-2.36 (m, 1H), 2.28-2.25(m, 0.5H), 2.18-2.13 (m, 0.5H). MS (ESI, method A): m/z=419.8 [M+H]⁺,t_(R)=1.429 min. HPLC: 97.2% (214 nm), 97.5% (254 nm).

ethyl 3-oxo-3-(4-phenoxyphenyl)propanoate (2)

To a mixture of diethyl carbonate (14 g, 120 mmol) and NaH (4.8 g, 120mmol) in toluene (100 mL) was added 1-(4-phenoxyphenyl)ethanone 1 (10 g,47 mmol) dropwise for 20 min. The resulting mixture was refluxed for 40min. When it cooled to rt, which was quenched with AcOH/H₂O (6 mL/30mL), then diluted with EA (100 mL). The organic layer was separated,washed with brine, dried over sodium sulfate, filtered and concentrated.The residue was applied onto silica gel column eluting with 20:1 PE/EAto get the title compound (7.5 g, 56%) as yellow oil. MS (ESI):m/z=285.1 [M+H]⁺.

ethyl 2-bromo-3-oxo-3-(4-phenoxyphenyl)propanoate (3)

To a mixture of ethyl 3-oxo-3-(4-phenoxyphenyl)propanoate 2 (6.55 g,23.1 mmol) in dioxane (100 mL) was added Br₂ (3.69 g, 23.1 mmol)dropwise at 0° C. under N₂. The resulting mixture was stirred at it for3 h. The volatile phase was removed under reduced pressure. Thisresulted in crude title compound (9.5 g, overweight) as yellow oil. MS(ESI): m/z=363.0/365.0 [M+H]⁺.

1-tert-butyl 3-(1-ethoxy-1,3-dioxo-3-(4-phenoxyphenyl)propan-2-yl)piperidine-1,3-dicarboxylate (4)

To a mixture of ethyl 2-bromo-3-oxo-3-(4-phenoxyphenyl)propanoate 3 (1.0g, 2.75 mmol) in CH₃CN (20 mL) was added DIEA (0.39 g, 3.0 mmol)dropwise. The resulting mixture was stirred at rt overnight. Thevolatile phase was removed under reduced pressure. The residue wasapplied onto silica gel column eluting with 3:1 PE/EA to get the titlecompound (1.15 g, 82%) as yellow oil. MS (ESI): m % z=412.1 [M+H−Boc]⁺.

ethyl 4-(4-phenoxyphenyl)-2-(piperidin-3-yl)oxazole-5-carboxylate (5)

A mixture of 1-tert-butyl3-(1-ethoxy-1,3-dioxo-3-(4-phenoxyphenyl)propan-2-yl)piperidine-1,3-dicarboxylate 4 (1.15 g, 2.25 mmol) and AcONH₄ (0.86 g,11.23 mmol) in AcOH (20 mL) was stirred at 120° C. for 2 h. The volatilephase was removed under reduced pressure. The residue was dissolved inEA (50 mL), which was washed with sat. NaHCO₃, brine, dried over sodiumsulfate, filtered and concentrated. This resulted in crude titlecompound (0.85 g, crude) as yellow oil. MS (ESI): m/z=393.1 [M+H]⁺.

Ethyl-2-(1-(tert-butoxycarbonyl)piperidin-3-yl)-4-(4-phenoxyphenyl)oxazole-5-carboxylate(6)

The title compound was obtained using a procedure analogous to theprocedure described in ethyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxylate(see Scheme 37) as pale yellow oil (0.35 g, 33%, two steps). MS (ESI):m/z=437.0 [M+H−56]⁺.

2-(1-(tert-butoxycarbonyl)piperidin-3-yl)-4-(4-phenoxyphenyl)oxazole-5-carboxylicacid (7)

The title compound was obtained using a procedure analogous to theprocedure described in5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4′-phenoxybiphenyl-2-carboxylicacid (see Scheme 45) as yellow oil (350 mg, overweight). MS (ESI):m/z=465.1 [M+H]⁺.

tert-butyl3-(5-carbamoyl-4-(4-phenoxyphenyl)oxazol-2-yl)piperidine-1-carboxylate(8)

The title compound was obtained using a procedure analogous to theprocedure described intert-butyl-3-(4-carbamoyl-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate(see Scheme 23) as pale yellow solid (250 mg, overweight). MS (ESI):m/z=408.0 [M+H−56]⁺.

4-(4-phenoxyphenyl)-2-(piperidin-3-yl)oxazole-5-carboxamidehydrochloride (9)

The title compound was obtained using a procedure analogous to theprocedure described in1-(4-phenoxyphenyl)-5-(piperidin-4-yl)-1H-pyrazole-3-carboxamidehydrochloride (see Scheme 46) as white solid (150 mg, overweight). MS(ESI): m/z=364.1 [M+H]⁺.

Example 422-(1-acryloylpiperidin-3-yl)-4-(4-phenoxyphenyl)oxazole-5-carboxamide

The title compound was obtained using a procedure analogous to theprocedure described below in Example 43 as white solid (60 mg, 45%, foursteps). ¹H NMR (300 MHz, DMSO) δ 8.26 (d, J=9.0 Hz, 2H), 7.92 (s, 1H),7.67 (s, 1H), 7.53-7.29 (m, 2H), 7.25-7.13 (m, 1H), 7.11-6.99 (m, 4H),6.85 (dd, J=16.7, 10.5 Hz, 1H), 6.11 (dd, J=16.7, 2.4 Hz, 1H), 5.68 (dd,J=10.4, 2.4 Hz, 1H), 4.39-4.31 (m, 1H), 4.12-4.04 (m, 1H), 3.33-3.14 (m,2H), 3.02-2.89 (m, 1H), 2.14-2.06 (m, 2H), 1.90-1.65 (m, 2H). MS (ESI,method A): m/z=418.1 [M+H]⁺, t_(R)=1.488 min. HPLC: 97% (214 nm), 97%(254 nm).

1-tert-butyl 3-(1-ethoxy-1,3-dioxo-3-(4-phenoxyphenyl)propan-2-yl)pyrrolidine-1,3-dicarboxylate (2)

The title compound was obtained using a procedure analogous to theprocedure described in 1-tert-butyl3-(1-ethoxy-1,3-dioxo-3-(4-phenoxyphenyl)propan-2-yl)piperidine-1,3-dicarboxylate (see Scheme 32) as pale yellow oil (1.1 g,80%). MS (ESI): m/z=441.8 [M+H−56]⁺.

ethyl 4-(4-phenoxyphenyl)-2-(pyrrolidin-3-yl)oxazole-5-carboxylate (3)

The title compound was obtained using a procedure analogous to theprocedure described in ethyl4-(4-phenoxyphenyl)-2-(piperidin-3-yl)oxazole-5-carboxylate (see Scheme32) as yellow oil (0.80 g, crude). MS (ESI): m/z=420.1 [M+H+41]⁺.

ethyl2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-(4-phenoxyphenyl)oxazole-5-carboxylate(4)

The title compound was obtained using a procedure analogous to theprocedure described in ethyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxylate(see Scheme 37) as pale yellow oil (0.35 g, 33%, two steps). MS (ESI):m/z=423.1 [M+H−56]⁺.

2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-(4-phenoxyphenyl)oxazole-5-carboxylicacid (5)

The title compound was obtained using a procedure analogous to theprocedure described in5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4′-phenoxybiphenyl-2-carboxylicacid (see Scheme 45) as yellow oil (350 mg, overweight). MS (ESI):m/z=395.0 [M+H−56]⁺.

tert-butyl3-(5-carbamoyl-4-(4-phenoxyphenyl)oxazol-2-yl)pyrrolidine-1-carboxylate(6)

The title compound was obtained using a procedure analogous to theprocedure described intert-butyl-3-(4-carbamoyl-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate(see Scheme 23) as pale yellow solid (250 mg, overweight). MS (ESI): m:=394.1 [M+H−56]⁺.

4-(4-phenoxyphenyl)-2-(pyrrolidin-3-yl)oxazole-5-carboxamidehydrochloride (7)

The title compound was obtained using a procedure analogous to theprocedure described in1-(4-phenoxyphenyl)-5-(piperidin-4-yl)-1H-pyrazole-3-carboxamidehydrochloride (see Scheme 46) as white solid (150 mg, overweight). MS(ESI): m/z=350.1 [M+H]⁺.

Example 432-(1-acryloylpyrrolidin-3-yl-4-(4-phenoxyphenyl)oxazole-5-carboxamide

The title compound was obtained using a procedure analogous to theprocedure described in Example 15 as white solid (45 mg, 34%, foursteps). ¹H NMR (400 MHz, DMSO) δ 8.27 (d, J=8.8 Hz, 2H), 7.94 (d, J=8.0Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.43 (t, J=7.9 Hz, 2H), 7.19 (t, J=7.9Hz, 1H), 7.11-7.02 (m, 4H), 6.69-6.55 (m, 1H), 6.19 (d, J=18.0 Hz, 1H),5.70 (d, J=10.4 Hz, 1H), 4.08-3.96 (m, 1H), 3.90-3.65 (m, 3H), 3.64-3.55(m, 0.5H), 3.53-3.45 (m, 0.5H), 2.45-2.37 (m, 1H), 2.36-2.27 (m, 1H). MS(ESI, method A): m/z=404.1 [M+H]⁺, t_(R)=1.542 min. HPLC: 98% (214 nm),98% (254 nm).

tert-butyl3-(1-ethoxy-1,3-dioxo-3-(4-phenoxyphenyl)propan-2-ylcarbamoyl)pyrrolidine-1

carboxylate (2). The title compound was obtained using a procedureanalogous to the procedure described in tert-butyl3-(1-ethoxy-1,3-dioxo-3-(4-phenoxyphenyl)propan-2-ylcarbamoyl)piperidine-1-carboxylate(see Scheme 35) as yellow oil (0.35 g, 30%). MS (ESI): m/z=440.7[M−55]⁺.

ethyl2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-5-(4-phenoxyphenyl)thiazole-4-carboxylate(3)

The title compound was obtained using a procedure analogous to theprocedure described in ethyl2-(1-(tert-butoxycarbonyl)piperidin-3-yl)-5-(4-phenoxyphenyl)thiazole-4-carboxylate(see Scheme 35) as yellow oil (0.12 g, 61%). MS (ESI): m % z=494.7[M+H]⁺.

2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-5-(4-phenoxyphenyl)thiazole-4-carboxylicacid (4)

The title compound was obtained using a procedure analogous to theprocedure described in5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-(4-phenoxyphenyl)-1H-pyrazole-3-carboxylic acid (see Scheme 46) as colorless oil (110 mg, 97%). MS (ESI):m/z=488.7 [M+Na]⁺.

tert-butyl3-(4-carbamoyl-5-(4-phenoxyphenyl)thiazol-2-yl)pyrrolidine-1-carboxylate(5)

The title compound was obtained using a procedure analogous to theprocedure described in tert-butyl 4-carbamoylpiperidine-1-carboxylate(see Scheme 42) as colorless oil (95 mg, 87%). MS (ESI): m % z=487.7[M+Na]⁺.

5-(4-phenoxyphenyl)-2-(pyrrolidin-3-yl)thiazole-4-carboxamidehydrochloride (6)

The title compound was obtained using a procedure analogous to theprocedure described in1-(4-phenoxyphenyl)-5-(piperidin-4-yl)-1H-pyrazole-3-carboxamidehydrochloride (see Scheme 46) as colorless oil (90 mg, 100%). MS (ESI):m/z=365.8 [M+H]⁺.

Example 442-(1-acryloylpyrrolidin-3-yl)-5-(4-phenoxyphenyl)thiazole-4-carboxamide

The title compound was obtained using a procedure analogous to theprocedure described in Example 3 as a white solid (30 mg, 30%). ¹H NMR(300 MHz, CD₃OD) δ 7.52 (d, J=9.0 Hz, 2H), 7.37 (d, J=9.0 Hz, 2H), 7.15(t, J=7.4 Hz, 1H), 7.06-7.02 (m, 2H), 6.99-6.94 (m, 2H), 6.64 (ddd,J=16.9, 10.4, 7.2 Hz, 1H), 6.29 (dt, J=16.8, 1.9 Hz, 1H), 5.76 (dt,J=10.4, 1.7 Hz, 1H), 4.19-4.05 (m, 0.5H), 4.03-3.82 (m, 3H), 3.83-3.71(m, 1H), 3.65-3.55 (m, 0.5H), 2.61-2.23 (m, 2H). MS (ESI, method F):m/z=419.7 [M+H]⁺, t_(R)=1.487 min. HPLC: 99.3% (214 nm), 98.7% (254 nm).

(E)-ethyl 2-(hydroxyimino)-3-oxo-3-(4-phenoxyphenyl)propanoate (2)

To a solution of ethyl 3-oxo-3-(4-phenoxyphenyl)propanoate 1 (1 g, 3.52mmol) in AcOH (15 mL) was added a solution of NaNO₂ (0.364 g, 5.28 mmol)in water (10 mL) at 0° C. The mixture was stirred at ambient temperaturefor 15 h. After finished, the mixture was extracted with ethyl acetate(2×20 mL). The organic layers were washed with water (2×10 mL) and brine(2×10 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated to give the title compound (1.1 g, 100%) as a yellow solid.MS (ESI): m/z=313.8 [M+H]⁺.

ethyl 2-amino-3-oxo-3-(4-phenoxyphenyl)propanoate hydrochloride (3)

To the solution of (E)-ethyl2-(hydroxyimino)-3-oxo-3-(4-phenoxyphenyl)propanoate 2 (6 g, 19.15 mmol)in MeOH (50 mL) was added Pd/C (10%, 500 mg) and HCl/EtOH (33%, 20 mL)under hydrogen atmosphere, and the resulting solution was stirred for 24h at ambient temperature, then filtered and the filtrate wasconcentrated. The crude product was purified by Prep-HPLC eluting withCH₃CN/H₂O (containing 0.5% TFA) from 10:90 to 60:40 to get the titlecompound (3.5 g, 61%) as yellow oil. MS (ESI): m/z=299.9 [M+H]⁺.

tert-butyl3-(1-ethoxy-1,3-dioxo-3-(4-phenoxyphenyl)propan-2-ylcarbamoyl)piperidine-1-carboxylate(4)

To the solution of 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid(0.5 g, 2.18 mmol) in DCM (10 mL) was added oxalyl chloride (0.415 g,3.27 mmol) and 5 drops of DMF. The mixture was stirred at rt for 2 h,concentrated to give the crude mixture. To the solution of ethyl2-amino-3-oxo-3-(4-phenoxyphenyl)propanoate hydrochloride 3 (0.73 g,2.18 mmol) in DCM (20 mL) was added TEA (0.66 g, 6.54 mmol) and asolution of above mixture in DCM (10 mL). The resulting solution wasstirred at rt for 2 h. The reaction mixture was washed with brine (2×10mL), dried over Na₂SO₄, filtered and concentrated to get a residue whichwas purified by silica gel column chromatography eluting with 1:1 PE/EAto get the title compound (0.16 g, 14%) as a yellow oil. MS (ESI):m/z=454.7 [M−55]⁺.

ethyl2-(1-(tert-butoxycarbonyl)piperidin-3-yl)-5-(4-phenoxyphenyl)thiazole-4-carboxylate(5)

To a solution of tert-butyl3-(1-ethoxy-1,3-dioxo-3-(4-phenoxyphenyl)propan-2-ylcarbamoyl)piperidine-1-carboxylate4 (0.16 g, 0.31 mmol) in THF (20 mL) was added lawesson's reagent (0.127g, 0.31 mmol). The mixture was degassed with N₂ for 3 times, then heatedto reflux and stirred for 2 h. When finished, the mixture was extractedwith ethyl acetate (2×20 mL). The organic layers were washed with sat.NaHCO₃ (2×20 mL) and brine (2×20 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated to get a residue which was purified bysilica gel column chromatography eluting with 2:1 PE/EA to get the titlecompound (90 mg, 57%) as a yellow oil. MS (ESI): m/z=508.8 [M+H]⁺.

2-(1-(tert-butoxycarbonyl)piperidin-3-yl)-5-(4-phenoxyphenyl)thiazole-4-carboxylicacid (6)

The title compound was obtained using a procedure analogous to theprocedure described in5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-(4-phenoxyphenyl)-1H-pyrazole-3-carboxylicacid (see Scheme 46) as a white solid (80 mg, 94%). MS (ESI): m/z=480.8[M+H]⁺.

tert-butyl3-(4-carbamoyl-5-(4-phenoxyphenyl)thiazol-2-yl)piperidine-1-carboxylate(7)

The title compound was obtained using a procedure analogous to theprocedure described in tert-butyl 4-carbamoylpiperidine-1-carboxylate(see Scheme 42) as colorless oil as colorless oil (40 mg, 50%). MS(ESI): m/z=479.7[M+H]⁺.

5-(4-phenoxyphenyl)-2-(piperidin-3-yl)thiazole-4-carboxamidehydrochloride (8)

The title compound was obtained using a procedure analogous to theprocedure described in1-(4-phenoxyphenyl)-5-(piperidin-4-yl)-1H-pyrazole-3-carboxamidehydrochloride (see Scheme 46) as yellow oil (35 mg, 100%). MS (ESI):m/z=379.8[M+H]⁺.

Example 452-(1-acryloylpiperidin-3-yl)-5-(4-phenoxyphenyl)thiazole-4-carboxamide

The title compound was obtained using a procedure analogous to theprocedure described in Example 3 as a white solid (10 mg, 27%). ¹H NMR(300 MHz, CD₃OD) δ 7.56-7.48 (m, 2H), 7.44-7.32 (m, 2H), 7.15 (t, J=7.4Hz, 1H), 7.03 (d, J=0.9 Hz, 2H), 6.99-6.94 (m, 2H), 6.84 (ddd, J=23.2,16.7, 10.6 Hz, 1H), 6.21 (dd, J=16.8, 1.9 Hz, 1H), 5.75 (d, J=10.7 Hz,1H), 4.62 (d, J=11.6 Hz, 0.5H), 4.27 (d, J=13.2 Hz, 0.5H), 4.15 (d,J=12.8 Hz, 0.5H), 4.00 (d, J=13.6 Hz, 0.5H), 3.72 (dd, J=13.5, 8.9 Hz,0.5H), 3.42-3.33 (m, 1H), 3.29-3.15 (m, 1.5H), 2.35-2.23 (m, 1H),2.08-1.85 (m, 2H), 1.75-1.55 (m, 1H). MS (ESI, method F): m/z=433.8[M+H]¹, t_(R)=1.557 min. HPLC: 96.7% (214 nm), 98.0% (254 nm).

1-tert-butyl 4-(1-ethoxy-1,3-dioxo-3-(4-phenoxyphenyl)propan-2-yl)piperidine-1,4-dicarboxylate (2)

The title compound was obtained using a procedure analogous to theprocedure described in 1-tert-butyl3-(1-ethoxy-1,3-dioxo-3-(4-phenoxyphenyl)propan-2-yl)piperidine-1,3-dicarboxylate (see Scheme 32) as pale yellow oil (0.85 g,60%). MS (ESI): m/z=456.1 [M+H−56]⁺

ethyl 4-(4-phenoxyphenyl)-2-(piperidin-4-yl)oxazole-5-carboxylate (3)

The title compound was obtained using a procedure analogous to theprocedure described in ethyl4-(4-phenoxyphenyl)-2-(piperidin-3-yl)oxazole-5-carboxylate (see Scheme32) as yellow oil (0.80 g, crude). MS (ESI): m/z=393.2 [M+H]⁺.

Ethyl-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-(4-phenoxyphenyl)oxazole-5-carboxylate(4)

The title compound was obtained using a procedure analogous to theprocedure described in ethyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxylate(see Scheme 37) as pale yellow oil (0.85 g, 68%, two steps). MS (ESI):m/z=437.2 [M+H−56]⁺.

2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-(4-phenoxyphenyl)oxazole-5-carboxylicacid (5)

The title compound was obtained using a procedure analogous to theprocedure described in5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4′-phenoxybiphenyl-2-carboxylicacid (see Scheme 45) as yellow oil (0.8 g, 99%). MS (ESI): m/z=409.1[M+H−56]⁺.

tert-butyl4-(5-carbamoyl-4-(4-phenoxyphenyl)oxazol-2-yl)piperidine-1-carboxylate(6)

The title compound was obtained using a procedure analogous to theprocedure described intert-butyl-3-(4-carbamoyl-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate(see Scheme 23) as pale yellow solid (390 mg, overweight). MS (ESI):m/z=408.0 [M+H−56]⁺.

4-(4-phenoxyphenyl)-2-(piperidin-4-yl)oxazole-5-carboxamidehydrochloride (7)

The title compound was obtained using a procedure analogous to theprocedure described in1-(4-phenoxyphenyl)-5-(piperidin-4-yl)-1H-pyrazole-3-carboxamidehydrochloride (see Scheme 46) as white solid (400 mg, overweight). MS(ESI): m/z=364.1 [M+H]⁺.

Example 462-(1-acryloylpiperidin-4-yl)-4-(4-phenoxyphenyl)oxazole-5-carboxamide

The title compound was obtained using a procedure analogous to theprocedure described in Example 15 as white solid (45 mg, 34%, threesteps). ¹H NMR (300 MHz, DMSO) δ 8.26 (d, J=9.0 Hz, 2H), 7.92 (s, 1H),7.674 (s, 1H), 7.53-7.29 (m, 2H), 7.25-7.13 (m, 1H), 7.11-6.99 (m, 4H),6.85 (dd, 1=16.7, 10.5 Hz, 1H), 6.11 (dd, J=16.7, 2.4 Hz, 1H), 5.68 (dd,J=10.4, 2.4 Hz, 1H), 4.39-4.31 (m, 1H), 4.12-4.04 (m, 1H), 3.33-3.14 (m,2H), 3.02-2.89 (m, 1H), 2.14-2.06 (m, 2H), 1.90-1.65 (m, 2H). MS (ESI,method A): m/z=418.1 [M+H]⁺, t_(R)=1.489 min. HPLC: 97% (214 nm), 97%(254 nm).

tert-butyl 4-carbamothioylpiperazine-1-carboxylate (3)

To a solution of di(1H-imidazol-1-yl)methanethione 2 (2.14 g, 12 mmol)in anhydrous THF (30 mL) was added tert-butyl piperazine-1-carboxylate 1(1.86 g, 10 mmol) at ambient temperature. The mixture was allowed tostir at ambient temperature for 2 h, then the mixture was heated at 55°C. for 1 h. The mixture was concentrated under vacuum to about half thevolume. To the remaining reaction mixture was added 2 M solution ofammonia in methanol (20 mL) and allowed to stir at ambient temperaturefor 3 days. The solvent was removed and the residue was purified bychromatography eluting with 50:1 DCM/MeOH to afford the title compound(1.7 g, 69%) as white solid. MS (ESI): m/z=246.1 [M+H]⁺.

ethyl 4-(4-phenoxyphenyl)-2-(piperazin-1-yl)thiazole-5-carboxylate (5)

To a solution of ethyl 2-bromo-3-oxo-3-(4-phenoxyphenyl)propanoate 4(362 mg, 1 mmol) in ethanol (10 mL) was added tert-butyl4-carbamothioylpiperazine-1-carboxylate 3 (245 mg, 1 mmol) at ambienttemperature. The mixture was then heated to reflux and stirred for 2 h.After cooling to ambient temperature, the solvent was removed and theresidue was purified by silica gel column chromatography eluting with40:1 to 20:1 DCM/MeOH to afford the title compound (214 mg, 52%) asbrown solid. MS (ESI): m/z=410.1 [M+H]⁺.

ethyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxylate(6)

To the compound of ethyl4-(4-phenoxyphenyl)-2-(piperazin-1-yl)thiazole-5-carboxylate 5 (214 mg,0.51 mmol) were added di-tert-butyl dicarbonate (134 mg, 0.6 mmol) andTEA (0.2 mL, 1.5 mmol) at ambient temperature. The mixture was thenstirred at ambient temperature for 2 h. The solvent was removed and theresidue was purified by silica gel column chromatography eluting with50:1 DCM/MeOH to afford the title compound (190 mg, 73%) as brown solid.MS (ESI): m/z=510.1 [M+H]⁺.

2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxylicacid (7)

To a solution of ethyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxylate6 (190 mg, 0.37 mmol) in THF (50 mL)/H₂O (1 mL)/MeOH (3 mL) was addedlithium hydroxide (30 mg, 0.74 mmol) at ambient temperature. The mixturewas then heated to 60° C. and stirred for 2 h. After cooling to ambienttemperature, the solvent was removed and the residue was purified bychromatography eluting with 10:1 DCM/MeOH to afford the title compound(173 mg, 97%) as white solid. MS (ESI): m/z=482.0 [M+H]⁺.

tert-butyl4-(5-(methylcarbamoyl)-4-(4-phenoxyphenyl)thiazol-2-yl)piperazine-1-carboxylate(8)

To a solution of2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxylicacid 7 (124 mg, 0.26 mmol) in DCM (10 mL) was added HATU (117 mg, 0.3mmol) and methanamine (0.26 ml, 0.26 mmol) at ambient temperature. Themixture was stirred at ambient temperature for 3 h. The solvent wasremoved and the residue was purified by silica gel column chromatographyeluting with 1:5 EA/PE to afford the title compound (115 mg, 90%) ascolorless oil. MS (ESI): m/z=495.2 [M+H]⁺.

N-methyl-4-(4-phenoxyphenyl)-2-(piperazin-1-yl)thiazole-5-carboxamide(9)

To a solution of tert-butyl4-(5-(methylcarbamoyl)-4-(4-phenoxyphenyl)thiazol-2-yl)piperazine-1-Carboxylate8 (115 mg, 0.23 mmol) in DCM (5 mL) was added TFA (1 mL) at ambienttemperature. The mixture was stirred for 1 h at ambient temperature. Thesolvent was removed and the residue was purified by silica gel columnchromatography eluting with 10:1 DCM/MeOH to afford the title compound(117 mg, 100%) as colorless oil.

Example 472-(4-acryloylpiperazin-1-yl)-N-methyl-4-(4-phenoxyphenyl)thiazole-5-carboxamide

To a solution ofN-methyl-4-(4-phenoxyphenyl)-2-(piperazin-1-yl)thiazole-5-carboxamide 9(117 mg, 0.23 mmol) in DCM (5 mL) were added TEA (0.1 mL, 0.7 mmol) andacryloyl chloride 10 (0.21 mg, 0.23 mmol) at 0° C. The mixture wasstirred at 0° C. for 10 minutes. The solvent was removed and the residuewas purified by Prep-TLC eluting with 50:1 to 20:1 DCM/MeOH to affordthe title compound (50 mg, 49%) as white solid. ¹H NMR (400 MHz, CDCl₃)57.57 (d, J=8.6 Hz, 2H), 7.40 (t, J=7.9 Hz, 2H), 7.19 (t, J=7.4 Hz, 1H),7.09 (d, J=8.4 Hz, 4H), 6.60 (dd, J=16.8, 10.5 Hz, 1H), 6.37 (d, J=16.7Hz, 1H), 5.79 (d, J=11.8 Hz, 1H), 5.59 (d, J=4.1 Hz, 1H), 3.78 (d,l=48.5 Hz, 4H), 3.62 (s, 4H), 2.80 (d, J=4.8 Hz, 3H), MS (ESI, methodA): m/z=449.1 [M+H]⁺, t_(R)=1.528 min. HPLC: 96.90% (214 nm), 96.9% (254nm).

tert-butyl-3-(1-ethoxy-1,3-dioxo-3-(4-phenoxyphenyl)propan-2-ylcarbamoyl)pyrrolidine-1-carboxylate(2)

The title compound was obtained using a procedure analogous to theprocedures described in the General Scheme and Example 15 as yellow oil(0.35 g, 30%). MS (ESI): m/z=440.7 [M−55]⁺.

Ethyl-2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-5-(4-phenoxyphenyl)oxazole-4-carboxylate(3)

To a solution of Ph₃P (159 mg, 0.604 mmol) in DCM (20 mL) was added I₂(153 mg, 0.604 mmol). The resulting mixture was degassed with N₂ 3 timesand stirred at ambient temperature for 2 h. TEA (122 mg, 1.208 mmol) wasadded and stirred for 10 min, then a solution of tert-butyl3-(1-ethoxy-1,3-dioxo-3-(4-phenoxyphenyl)propan-2-ylcarbamoyl)pyrrolidine-1-carboxylate2 (150 mg, 0.302 mmol) was added and stirred for 15 h. The mixture wasdiluted with ethyl acetate (50 mL), and washed with sat. Na₂S₂O₃ (20mL), brine (3×20 mL). The organic layer was dried over Na₂SO₄, filteredand concentrated to get a residue which was purified by silica gelcolumn chromatography eluting with 1:1 PE/EA to get the title compound(0.11 g, 76%) as a colorless oil. MS (ESI): m/z=422.8 [M−55]⁺.

2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-5-(4-phenoxyphenyl)oxazole-4-carboxylicacid (4)

The title compound was obtained using a procedure analogous to theprocedure described in5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-(4-phenoxyphenyl)-1H-pyrazole-3-carboxylicacid (see Scheme 46) as yellow oil (110 mg, 100%). MS (ESI): m/z=394.8[M−55]⁺

tert-butyl3-(4-carbamoyl-5-(4-phenoxyphenyl)oxazol-2-yl)pyrrolidine-1-carboxylate(5)

The title compound was obtained using a procedure analogous to theprocedure described in tert-butyl 4-carbamoylpiperidine-1-carboxylate(see Scheme 42) as colorless oil (95 mg, 92%). MS (ESI): m/z=393.8[M−55]⁺.

5-(4-phenoxyphenyl)-2-(pyrrolidin-3-yl)oxazole-4-carboxamidehydrochloride (6)

The title compound was obtained using a procedure analogous to theprocedure described in1-(4-phenoxyphenyl)-5-(piperidin-4-yl)-1H-pyrazole-3-carboxamidehydrochloride (see Scheme 46) as a white solid (75 mg, 92%). MS (ESI):m/z=349.9 [M+H]⁺.

Example 482-(1-acryloylpyrrolidin-3-yl)-5-(4-phenoxyphenyl)oxazole-4-carboxamide

The title compound was obtained using a procedure analogous to theprocedure described in Example 1 as an off white solid (50 mg, 64%). ¹HNMR (400 MHz, DMSO) δ 8.27-8.22 (m, 2H), 7.61 (s, 1H), 7.58 (s, 1H),7.45 (t, J=7.9 Hz, 2H), 7.21 (t, J=7.3 Hz, 1H), 7.14-7.06 (m, 4H),6.67-6.58 (m, 1H), 6.16 (d, J=16.7 Hz, 1H), 5.70 (d, J=10.4 Hz, 1H),4.05-4.01 (m, 0.5H), 3.97-3.92 (m, 0.5H), 3.90-3.59 (m, 3.5H), 3.53-3.45(m, 0.5H), 2.45-2.21 (m, 2H). MS (ESI, method A): m/z=404.1 [M+H]⁺,t_(R)=1.484 min. HPLC: 99.5% (214 nm), 99.3% (254 nm)

tert-butyl-4-(1-ethoxy-1,3-dioxo-3-(4-phenoxyphenyl)propan-2-ylcarbamoyl)piperidine-1carboxylate (2)

The title compound was obtained using a procedure analogous to theprocedures described in the General Scheme and Example 15 as colorlessoil (0.18 g, 16%). MS (ESI): m/z=454.8[M−55]⁺

ethyl2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-(4-phenoxyphenyl)thiazole-4-carboxylate(3)

The title compound was obtained using a procedure analogous to theprocedure described in tert-butyl2-carbamothioylpiperidine-1-carboxylate (see Scheme 30) as colorless oil(0.12 g, 67%). MS (ESI): m/z=508.8 [M+H]⁺.

2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-(4-phenoxyphenyl)thiazole-4-carboxylicacid (4)

The title compound was obtained using a procedure analogous to theprocedure described in5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-(4-phenoxyphenyl)-1H-pyrazole-3-carboxylic acid (see Scheme 46) as yellow oil (120 mg, 100%). MS (ESI): m/z=480.8[M+H]⁺.

tert-butyl4-(4-carbamoyl-5-(4-phenoxyphenyl)thiazol-2-yl)piperidine-1-carboxylate(5)

The title compound was obtained using a procedure analogous to theprocedure described in tert-butyl3-(5-carbamoyl-4-(4-phenoxyphenyl)thiazol-2-yl)piperidine-1-carboxylate(see Scheme 30) as colorless oil (100 mg, 88%). MS (ESI):m/z=479.8[M+H]⁺.

5-(4-phenoxyphenyl)-2-(piperidin-4-yl)thiazole-4-carboxamidehydrochloride (6)

The title compound was obtained using a procedure analogous to theprocedure described in1-(4-phenoxyphenyl)-5-(piperidin-4-yl)-1H-pyrazole-3-carboxamidehydrochloride (see Scheme 46) as a white solid (80 mg, 92%). MS (ESI):m/z=379.8[M+H]⁺.

Example 492-(1-acryloylpiperidin-4-yl)-5-(4-phenoxyphenyl)thiazole-4-carboxamide

The title compound was obtained using a procedure analogous to theprocedure described in Example 51 as an off white solid (20 mg, 24%). ¹HNMR (400 MHz, DMSO) δ 7.68 (s, 1H), 7.56 (d, J=8.7 Hz, 2H), 7.50 (s,1H), 7.47-7.42 (m, 2H), 7.21 (t, J=7.4 Hz, 1H), 7.10 (d, J=7.7 Hz, 2H),7.00 (d, J-=8.7 Hz, 2H), 6.85 (dd, J=16.7, 10.5 Hz, 1H), 6.12 (dd,J=16.7, 2.4 Hz, 1H), 5.69 (dd, J=10.5, 2.4 Hz, 1H), 4.49 (d, J=12.8 Hz,1H), 4.15 (d, J=12.8 Hz, 1H), 3.33-3.19 (m, 2H), 2.88 (d, J=11.5 Hz,1H), 2.12 (d, J=12.8 Hz, 2H), 1.73-1.55 (m, 2H). MS (ESI, method A):m/z=434.0 [M+H]⁺, t_(R)=1.606 min. HPLC: 95.0% (214 nm), 96.6% (254 nm)

Example 501-(1-(2-cyanoacetyl)azetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide

To a solution of1-(azetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide 7 (SeeExample 15 scheme, associated data and procedures) (900 mg, 2.4 mmol),2-cyanoacetic acid (178 mg, 2.1 mmol), EDCI (534 mg, 2.8 mmol) and HOBT(64 mg, 0.48 mmol) in dry DCM (20 mL) was added DIPEA (936 mg, 7.2 mmol)at 0° C. Then the solution was allowed to warm to rt slowly and stirredat rt for 3 h. After the reaction was completed, the solution was washedwith water (2×20 mL) and brine (2×20 mL). The organic layer was driedover anhydrous sodium sulfate, filtered and concentrated. The residuewas purified by silica gel column eluting with 30:1 DCM/MeOH to affordthe title compound (250 mg, 26%) as white solid. ¹H NMR (400 MHz, CDCl₃)δ 8.18 (s, 1H), 7.61-7.50 (m, 2H), 7.43-7.32 (m, 2H), 7.20-7.13 (m, 1H),7.12-7.03 (m, 4H), 5.65 (s, 2H), 5.24-5.14 (m, 1H), 4.87-4.73 (m, 2H),4.62-4.49 (m, 2H), 3.35 (s, 2H). MS (ESI, Method A): m/z=402.1 [M+H]⁺,t_(R)=1.361 min. HPLC: 98.0% (214 nm), 98.6% (254 nm).

tert-butyl 4-carbamothioylpiperazine-1-carboxylate (3)

To a solution of di(1H-imidazol-1-yl)methanethione 2 (2.14 g, 12 mmol)in anhydrous THF (30 mL) was added tert-butyl piperazine-1-carboxylate 1(1.86 g, 10 mmol) at ambient temperature. The mixture was allowed tostir at ambient temperature for 2 h, and then the mixture was heated to55° C. for 1 h. The mixture was concentrated in vacuum to about half thevolume. To the remaining reaction mixture was added a 2 M ammonia inmethanol (20 mL) and was allowed to stir at ambient temperature for 3days. The solvent was removed and the residue was purified by silica gelcolumn chromatography eluting with 50:1 DCM/MeOH to afford the titlecompound (1.7 g, 69%) as white solid. MS (ESI): m/z=246.1 [M+H]⁺.

ethyl 4-(4-phenoxyphenyl)-2-(piperazin-1-yl)thiazole-5-carboxylate (5)

To a solution of ethyl 2-bromo-3-oxo-3-(4-phenoxyphenyl)propanoate 4(362 mg, 1 mmol) in ethanol (10 mL) was added tert-butyl4-carbamothioylpiperazine-1-carboxylate 3 (245 mg, 1 mmol) at ambienttemperature. The mixture was then heated to reflux and stirred for 2 h.After cooling to ambient temperature, the solvent was removed and theresidue was purified by silica gel column chromatography eluting with40:1 to 20:1 DCM/MeOH to afford the title compound (214 mg, 52%) asbrown solid. MS (ESI): m/z=410.1 [M+H]⁺.

Ethyl-2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxylate(6)

To the compound of ethyl4-(4-phenoxyphenyl)-2-(piperazin-1-yl)thiazole-5-carboxylate 5 (214 mg,0.51 mmol) was added di-tert-butyl dicarbonate (134 mg, 0.6 mmol) andTEA (0.2 mL, 1.5 mmol) at ambient temperature. The mixture was thenstirred at ambient temperature for 2 h. The solvent was removed and theresidue was purified by silica gel column chromatography eluting with50:1 DCM/MeOH to afford the title compound (190 mg, 73%) as brown solid.MS (ESI): m/z=510.1 [M+H]⁺.

2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxylicacid (7)

To a solution of ethyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxylate6 (190 mg, 0.37 mmol) in THF (50 mL)/H₂O (1 mL)/MeOH (3 mL) was addedlithium hydroxide (30 mg, 0.74 mmol) at ambient temperature. The mixturewas then heated to 60° C. and stirred for 2 h. After cooling to ambienttemperature, the solvent was removed and the residue was purified bysilica gel column chromatography eluting with 10:1 DCM/MeOH to affordthe title compound (173 mg, 97%) as white solid. MS (ESI): m/z=482.0[M+H]⁺.

tert-butyl4-(5-carbamoyl-4-(4-phenoxyphenyl)thiazol-2-yl)piperazine-1-carboxylate(8)

To a solution of2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxylicacid 7 (173 mg, 4.6 mmol) in DCM (10 mL) was added HATU (164 mg, 0.43mmol) at ambient temperature. The mixture was degassed three times withammonia gas and stirred at ambient temperature under ammonia atmospherefor 6 h. The solvent was removed and the residue was purified by silicagel column chromatography eluting with 30:1 DCM/MeOH to afford the titlecompound (170 mg, 100%) as white solid. MS (ESI): m/z=481.1 [M+H]⁺.

4-(4-phenoxyphenyl)-2-(piperazin-1-yl)thiazole-5-carboxamide (9)

A solution of tert-butyl4-(5-carbamoyl-4-(4-phenoxyphenyl)thiazol-2-yl)piperazine-1-carboxylate8 (170 mg, 0.35 mmol) in DCM (5 mL) and TFA (1 mL) at ambienttemperature was stirred for 1 h. The solvent was removed and the residuewas purified by silica gel column chromatography eluting with 20:1 to10:1 DCM/MeOH to afford the title compound (110 mg, 58%) as white solid.

Example 512-(4-acryloylpiperazin-1-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxamide

To a solution of4-(4-phenoxyphenyl)-2-(piperazin-1-yl)thiazole-5-carboxamide 9 (110 mg,0.22 mmol) in DCM (5 mL) was added TEA (0.1 mL, 0.66 mmol) and acryloylchloride 10 (0.20 mg, 0.22 mmol) at 0° C. The mixture was stirred at 0°C. for 10 minutes. The solvent was removed and the residue was purifiedby Prep-TLC eluting with 25:1 DCM/MeOH to afford the title compound (70mg, 73%) as white solid. ¹H NMR (400 MHz, MeOD) δ 7.66-7.61 (m, 2H),7.37-7.43 (m, 2H), 7.18 (t, J=7.4 Hz, 1H), 7.10-7.04 (m, 4H), 6.83 (dd,J=16.8, 10.6 Hz, 1H), 6.27 (dd, J=16.8, 1.8 Hz, 1H), 5.81 (dd, J=10.6,1.9 Hz, 1H), 3.87-3.78 (m, 4H), 3.69-3.61 (m, 4H). MS (ESI, method A):m/z=435.0 [M+H]¹, t_(R)=1.539 min., HPLC: 95.5% (214 nm), 96.4% (254nm).

tert-butyl 4-carbamoylpiperidine-1-carboxylate (2)

To a mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid 1(2.29 g, 10 mmol), DIEA (3.87 g, 30 mmol) and HATU (4.18 g, 11 mmol) inDMF (50 mL) was added NH₃ by bubbling for 20 min. The resulting mixturewas stirred at rt overnight. The mixture was diluted with water (200 mL)and extracted with EA (2×50 mL). The organic layers were combined,washed with brine, dried over sodium sulfate, filtered and concentrated.The residue was applied onto silica gel column eluting with EA to getthe title compound (1.3 g, 56%) as white solid. MS (ESI): m z=173.2[M+H−56]⁺.

tert-butyl 4-carbamothioylpiperidine-1-carboxylate (3)

The title compound was obtained using a procedure analogous to theprocedure described in cyclopentanecarbothioamide (see Scheme 30) aspale yellow solid (0.35 g, 29%). MS (ESI): m/z=245.2 [M+H]⁺.

ethyl 4-(4-phenoxyphenyl)-2-(piperidin-4-yl)thiazole-5-carboxylate (5)

The crude of the title compound was obtained using a procedure analogousto the procedure described in ethyl2-cyclopentyl-4-(4-phenoxyphenyl)thiazole-5-carboxylate (see Scheme A-2)as yellow oil (0.90 g, overweight). MS (ESI): m/z=408.8 [M+H]⁺.

ethyl 4-(4-phenoxyphenyl)-2-(piperidin-4-yl)thiazole-5-carboxylate (6)

The title compound was obtained using a procedure analogous to theprocedure described in ethyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxylate(see Scheme 37) as yellow solid (0.30 g, 30° %, two steps). MS (ESI):m/z=509.1 [M+H]⁺.

2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxylicacid (7)

The title compound was obtained using a procedure analogous to theprocedure described in5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4′-phenoxybiphenyl-2-carboxylicacid (see Scheme 45) as yellow oil (250 mg, overweight). MS (ESI):m/z=481.0 [M+H]⁺.

tert-butyl4-(5-carbamoyl-4-(4-phenoxyphenyl)thiazol-2-yl)piperidine-1-carboxylate(8)

The title compound was obtained using a procedure analogous to theprocedure described intert-butyl-3-(4-carbamoyl-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate(see Scheme 23) as pale yellow solid (250 mg, overweight). MS (ESI): m,=480.1 [M+H]⁺.

4-(4-phenoxyphenyl)-2-(piperidin-4-yl)thiazole-5-carboxamide (9)

The title compound was obtained using a procedure analogous to theprocedure described in1-(4-phenoxyphenyl)-5-(piperidin-4-yl)-1H-pyrazole-3-carboxamidehydrochloride (see Scheme 46) as white solid (300 mg, overweight). MS(ESI): m/z=380.1 [M+H]⁺.

Example 522-(1-acryloylpiperidin-4-yl)-4-(4-phenoxyphenyl)thiazole-5-carboxamide

The title compound was obtained using a procedure analogous to theprocedure described in Example 15 as white solid (50 mg, 23%, foursteps). ¹H NMR (300 MHz, DMSO) δ 7.76-7.69 (m, 4H), 7.42 (t, J=7.4 Hz,2H), 7.19 (t, J=7.4 Hz, 1H), 7.09-7.00 (m, 4H), 6.84 (dd, J=16.7, 10.4Hz, 1H), 6.10 (dd, J=16.7, 2.4 Hz, 1H), 5.68 (dd, J=10.4, 2.4 Hz, 1H),4.52-4.41 (m, 1H), 4.19-4.08 (m, 1H), 3.32-3.15 (m, 2H), 2.90-2.78 (m,1H), 2.14-2.06 (m, 2H), 1.73-1.46 (m, 2H). MS (ESI, method A): m/z:=434.0 [M+H]⁺, t_(R)=1.540 min. HPLC: 96% (214 nm), 96% (254 nm)

Example 53(E)-1-(1-(2-cyano-3-cyclopropylacryloyl)azetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide

To a solution of1-(1-(2-cyanoacetyl)azetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide(100 mg, 0.25 mmol) and piperidine (2 drops) in EtOH (10 mL) was addedcyclopropanecarbaldehyde (70 mg, 1.0 mmol). Then the solution wasstirred at 70° C. for 1 h. After the reaction was completed, thesolution was concentrated and purified by Prep-TLC with 10:1 DCM/MeOH togive the crude product (70 mg) and then purified by Prep-HPLC(ACN/H₂O=42%, 0.1% FA) to afford the title compound (15 mg, 13%) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.64-7.57 (m, 2H),7.45-7.37 (m, 2H), 7.22-7.16 (m, 1H), 7.15-7.03 (m, 5H), 5.60 (s, 2H),5.23-5.13 (m, 1H), 5.11-4.95 (m, 2H), 4.68-4.54 (m, 2H), 2.16-2.05 (m,1H), 1.33-1.29 (m, 2H), 1.02-0.95 (m, 2H). MS (ESI, Method A): m/z=454.1[M+H]⁺, t_(R)=1.485 min. HPLC: 100% (214 nm), 100% (254 nm).

tert-butyl-3-(1-ethoxy-1,3-dioxo-3-(4-phenoxyphenyl)propan-2-ylcarbamoyl)piperidine-1-carboxylate(2)

The title compound was obtained using a procedure analogous to theprocedures described in the General Scheme and Example 15 as yellow oil(0.4 g, 36%). MS (ESI): m/z=454.8 [M−55]⁺.

Ethyl-2-(1-(tert-butoxycarbonyl)piperidin-3-yl)-5-(4-phenoxyphenyl)oxazole-4-carboxylate(3)

The title compound was obtained using a procedure analogous to theprocedure described in ethyl2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-5-(4-phenoxyphenyl)oxazole-4-carboxylate(see Scheme 44) as yellow oil (0.25 g, 65%). MS (ESI): m/z=492.8 [M+H]⁺.

2-(1-(tert-butoxycarbonyl)piperidin-3-yl)-5-(4-phenoxyphenyl)oxazole-4-carboxylicacid (4)

The title compound was obtained using a procedure analogous to theprocedure described in5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-(4-phenoxyphenyl)-1H-pyrazole-3-carboxylicacid (see Scheme 46) as yellow oil (0.25 g, 100%). MS (ESI): m % z=464.8[M+H]⁺.

tert-butyl3-(4-carbamoyl-5-(4-phenoxyphenyl)oxazol-2-yl)piperidine-1-carboxylate(5)

The title compound was obtained using a procedure analogous to theprocedure described in tert-butyl3-(5-carbamoyl-4-(4-phenoxyphenyl)thiazol-2-yl)piperidine-1-carboxylate(see Scheme 30) as yellow oil (0.2 g, 84%). MS (ESI): m/z=407.8 [M−55]⁺.

5-(4-phenoxyphenyl)-2-(piperidin-3-yl)oxazole-4-carboxamidehydrochloride (6)

The title compound was obtained using a procedure analogous to theprocedure described in1-(4-phenoxyphenyl)-5-(piperidin-4-yl)-1H-pyrazole-3-carboxamidehydrochloride (see Scheme 46) as brown oil (180 mg, 100%). MS (ESI):m/z=363.8[M+H]⁺.

Example 542-(1-acryloylpiperidin-3-yl)-5-(4-phenoxyphenyl)oxazole-4-carboxamide

The title compound was obtained using a procedure analogous to theprocedure described in Example 1 as a yellow solid (70 mg, 37%). ¹H NMR(400 MHz, DMSO) δ 8.24 (d, J=7.2 Hz, 2H), 7.57 (s, 1.5H), 7.50 (s,0.5H), 7.45 (t, J=7.9 Hz, 2H), 7.21 (t, J=7.4 Hz, 1H), 7.11 (d, J=3.1Hz, 2H), 7.08 (d, J=4.2 Hz, 2H), 6.96-6.78 (m, 1H), 6.13 (t, J=18 Hz,1H), 5.75-5.57 (m, 1H), 4.51 (d, J=11.6 Hz, 0.5H), 4.08 (d, J=12 Hz,0.5H), 3.93 (d, J=13.2 Hz, 0.5H), 3.85-3.73 (m, 0.8H), 3.34-3.20 (m,2H), 3.10-2.97 (m, 0.7H), 2.27-2.09 (m, 1H), 2.07-1.64 (m, 2H),1.60-1.43 (m, 1H). MS (ESI, method F): m/z=418.1 [M+H]⁺, t_(R)=1.679(min). HPLC: 100% (214 nm), 100% (254 nm).

ethyl 4-bromo-2-chlorobenzoate (2)

To a mixture of 4-bromo-2-chlorobenzoic acid 1 (1.9 g, 8.1 mmol) in EtOH(50 mL) was added H₂SO₄ (5 mL) dropwise carefully at 0° C. The resultingmixture was refluxed overnight. The volatile phase removed under reducedpressure. The residue was diluted with EA (100 mL), which was washedwith water (2×50 mL) and brine, dried over sodium sulfate, filtered andconcentrated. This resulted in the title compound (2.0 g, 95%) as brownoil. MS (ESI): m/z=263.0/265.0 [M+H]⁺.

tert-butyl4-(3-chloro-4-(ethoxycarbonyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate(3)

A mixture of ethyl 4-bromo-2-chlorobenzoate 2 (0.53 g, 2.0 mmol),tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(0.74 g, 2.4 mmol), potassium carbonate (0.83 g, 6.0 mmol) andPd(dppf)Cl₂ (0.15 g, 0.2 mmol) in dioxane/H₂O (20 mL/5 mL) was stirredat 80° C. for 4 h under N₂ atmosphere. The volatile phase was removedunder reduced pressure. The residue was applied onto silica gel columneluting with 6:1 PE/EA to get the title compound (0.7 g, 96%) as yellowoil. MS (ESI): m/z=310.1 [M+H−56]r.

tert-butyl4-(6-(ethoxycarbonyl)-4′-phenoxybiphenyl-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate(4)

A mixture of tert-butyl4-(3-chloro-4-(ethoxycarbonyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate3 (200 mg, 0.66 mmol), 4-phenoxyphenylboronic acid (172 mg, 0.80 mmol),K₃PO₄ (414 mg, 2.0 mmol), tricyclohexylphosphine (40 mg, 0.14 mmol) andPd₂(dba)₃ (64 mg, 0.07 mmol) in dioxane/H₂O (15 mL/3 mL) was stirred at110° C. overnight under N₂ atmosphere. The volatile phase was removedunder reduced pressure. The residue was applied onto silica gel columneluting with 6:1 PE/EA to get the title compound (200 mg, 61%) as yellowoil. MS (ESI): m/z=500.0 [M+H]⁺.

tert-butyl4-(6-(ethoxycarbonyl)-4′-phenoxybiphenyl-3-yl)piperidine-1-carboxylate(5)

A mixture of4-(6-(ethoxycarbonyl)-4′-phenoxybiphenyl-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate4 (180 mg, 0.36 mmol) and Pd/C (wet 10%, 18 mg) in MeOH (10 mL) wasstirred at rt under H₂ atmosphere for 5 h. The solid was filtered offand the filtrate was concentrated under reduced pressure. This resultedin the title compound (180 mg, 99%) as colorless oil, which was useddirectly for the next step. MS (ESI): m/z=524.0 [M+Na]⁺.

5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4′-phenoxybiphenyl-2-carboxylicacid (6)

A mixture of tert-butyl4-(6-(ethoxycarbonyl)-4′-phenoxybiphenyl-3-yl)piperidine-1-carboxylate 5(180 mg, 0.36 mmol) and NaOH (72 mg, 1.8 mmol) in THF/MeOH/H₂O (5 mL/5mL/5 mL) was stirred at rt overnight. The volatile phase was removedunder reduced pressure. The PH of which was adjusted to 3 by HCl (1 N),which was extracted with EA (2×30 mL). The organic layers were combined,washed with brine, dried over sodium sulfate, filtered and concentrated.This resulted in the title compound (180 mg, overweight) in colorlessoil, which was used directly for the next step. MS (ESI): m/z=374.1[M+H−Boc]⁺.

tert-butyl4-(6-carbamoyl-4′-phenoxybiphenyl-3-yl)piperidine-1-carboxylate (7)

The title compound was obtained using a procedure analogous to theprocedure described intert-butyl-3-(4-carbamoyl-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate(see Scheme 23) as pale yellow solid (200 mg, overweight). MS (ESI):m/z=416.8 [M+H−56]⁺.

tert-butyl4-(6-carbamoyl-4′-phenoxybiphenyl-3-yl)piperidine-1-carboxylate (8)

The title compound was obtained using a procedure analogous to theprocedure described in1-(4-phenoxyphenyl)-5-(piperidin-4-yl)-1H-pyrazole-3-carboxamidehydrochloride (see Scheme 46) as white solid (200 mg, overweight). MS(ESI): m/z=373.1 [M+H]⁺.

Example 55 5-(1-acryloylpiperidin-4-yl)-4′-phenoxybiphenyl-2-carboxamide

The title compound was obtained using a procedure analogous to theprocedure described in Example 61 as white solid (70 mg, 20%). ¹H NMR(300 MHz, CDCl₃) δ 7.75 (d, J=7.9 Hz, 1H), 7.44-7.32 (m, 4H), 7.23-7.28(m, 1H), 7.20-7.12 (m, 2H), 7.11-6.99 (m, 4H), 6.62 (dd, J=16.5 Hz, 10.5Hz, 1H), 6.31 (dd, J=16.5 Hz, 1.8 Hz, 1H), 5.73 (brs, 1H), 5.71 (dd,J=10.5 Hz, 1.8 Hz, 1H), 5.35 (brs, 1H), 4.99-4.74 (m, 1H), 4.24-4.03 (m,1H), 3.30-3.05 (m, 1H), 2.97-2.58 (m, 2H), 2.04-1.88 (m, 2H), 1.83-1.58(m, 2H). MS (ESI, method A): m/z=427.1 [M+H]⁺, t_(R)=1.563 min. HPLC:99% (214 nm), 99% (254 nm).

(4-phenoxyphenyl)hydrazine (2)

To a solution of 4-phenoxybenzenamine 1 (1.0 g, 5.4 mmol) in HCl (100mL) was added NaNO₂ (700 mg, 10.1 mmol) at 0° C. Then the mixture wasstirred at 0° C. for 1 h. A solution of SnCl₂ (5.0 g, 22.1 mmol) in HCl(100 mL) was added to the mixture, and the resulting mixture was stirredat rt for 3 h. Aqueous NaOH (3N) was added to adjust pH to 10, and themixture was extracted with EA (3×50 mL), the combined organic phase waswashed with brine (20 mL), dried over Na₂SO₄. The solvent was removedunder reduced pressure to give a crude title compound (567 mg, 56%) as ayellow solid, which was used to next step without further purification.MS (ESI): m/z=201.0 [M+H]⁺.

ethyl 5-hydroxy-1-(4-phenoxyphenyl)-1H-pyrazole-3-carboxylate (4)

To the solution of diethyl fumarate 3 (260 mg, 1.5 mmol) in EtOH (25 mL)was added (4-phenoxyphenyl)hydrazine 2 (254 mg, 1.3 mmol), and theresulting solution was stirred overnight at 80° C. The solvent wasevaporated under vacuum and the crude residue was diluted with water (30mL). The solution was extracted with ethyl acetate (3×30 mL). Theorganic layers were combined, dried over anhydrous sodium sulfate,filtered and concentrated. The residue was purified by silica gel columnchromatography eluting with 20:1 DCM/MeOH to afford the title compound(174 mg, 42%) as a yellow solid. MS (ESI): m/z=325.1 [M+H]⁺.

ethyl1-(4-phenoxyphenyl)-5-(trifuoromethylsulfonyloxy)-1H-pyrazole-3-carboxylate(6)

To a solution of ethyl5-hydroxy-1-(4-phenoxyphenyl)-1H-pyrazole-3-carboxylate 4 (170 mg, 0.5mmol) in DCM (20 mL) was added trifluoromethanesulfonic anhydride 5 (295mg, 1.0 mmol) and stirred for 1 h at −30° C. under N₂ atmosphere. Themixture was poured into water (60 mL), and the solution was extractedwith ethyl acetate (3×30 mL). The organic layers were combined, driedover anhydrous sodium sulfate, filtered and concentrated. The residuewas purified by silica gel column chromatography eluting with 5:1 PE/EAto afford the title compound (210 mg, 92%) as a yellow solid. MS (ESI):m/z=457.0 [M+H]⁺.

tert-butyl-4-(3-(ethoxycarbonyl)-1-(4-phenoxyphenyl)-1H-pyrazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate(8)

To a solution of ethyl1-(4-phenoxyphenyl)-5-(trifluoromethylsulfonyloxy)-1H-pyrazole-3-carboxylate6 (210 mg, 0.5 mmol), K₂CO₃ (552 mg, 4.0 mmol) and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate7 (201 mg, 0.6 mmol) in dioxane/H₂O (10:1, 20 mL) was added Pd(dppf)Cl₂(327 mg, 0.2 mmol) under nitrogen atmosphere, and the mixture wasdegassed with nitrogen 6 times, then heated to 90° C. and stirredovernight under nitrogen atmosphere. After cooling to room temperature,the solvent was evaporated and the crude product was purified by silicagel column chromatography eluting with 20:1 DCM/MeOH to afford the titlecompound (95 mg, 42%) as a yellow solid. MS (ESI): m/z=490.2[M+H]⁺.

tert-butyl-4-(3-(ethoxycarbonyl)-1-(4-phenoxyphenyl)-1H-pyrazol-5-yl)piperidine-1-carboxylate(9)

The mixture of tert-butyl4-(3-(ethoxycarbonyl)-1-(4-phenoxyphenyl)-1H-pyrazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate8 (95 mg, 0.2 mmol), Pd/C (10% palladium on carbon, 56.5% water, 48 mg)and MeOH (20 mL) was degassed with H₂ 6 times and then stirred under H₂at rt for 1 h. Then the mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (56 mg, 58%) ascolorless oil. MS (ESI): m/z=492.2 [M+H]⁺.

5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-(4-phenoxyphenyl)-1H-pyrazole-3-carboxylicacid (10)

To the solution of tert-butyl4-(3-(ethoxycarbonyl)-1-(4-phenoxyphenyl)-1H-pyrazol-5-yl)piperidine-1-carboxylate9 (166 mg, 0.3 mmol) in THF/MeOH/H₂O (20:20:10 mL) was added LiOH (60mg, 1.4 mmol), and the resulting solution was stirred for 15 h atambient temperature. The mixture was concentrated, the residue wasdiluted with water (10 mL), and the solution was acidified with citricacid to pH=4, extracted with ethyl acetate (3×20 mL), washed with brine(20 mL), dried over Na₂SO₄, filtered and concentrated to get the titlecompound (120 mg, 76%) as a brown solid. MS (ESI): m/z=464.2 [M+H]⁺

tert-butyl-4-(3-carbamoyl-1-(4-phenoxyphenyl)-1H-pyrazol-5-yl)piperidine-1-carboxylate(11)

To a solution of5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-(4-phenoxyphenyl)-1H-pyrazole-3-carboxylicacid 10 (250 mg, 0.59 mmol) and HATU (147 mg, 0.38 mmol) in dryN,N-dimethyl formamide (25 mL) was added DIPEA (67 mg, 0.51 mmol), andthe resulting solution was stirred for 20 min at ambient temperature,then NH₄Cl (28 mg, 0.51 mmol) was added and stirred overnight. Themixture was diluted with ethyl acetate (50 mL), and washed with water(2×20 mL) and brine (2×20 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated to get a residue which was purified by silicagel column chromatography eluting with 20:1 DCM/MeOH to afford the titlecompound (100 mg, 84%) as a yellow solid. MS (ESI): m/z=463.2 [M+H]⁺.

1-(4-phenoxyphenyl)-5-(piperidin-4-yl)-1H-pyrazole-3-carboxamidehydrochloride (12)

To a solution of tert-butyl4-(3-carbamoyl-1-(4-phenoxyphenyl)-1H-pyrazol-5-yl)piperidine-1-carboxylate11 (100 mg, 0.21 mmol) in EtOH (20 mL) was added HCl/EtOH (33%, 2 mL) atambient temperature. The mixture was stirred for 12 h at roomtemperature. The mixture concentrated to give the title compound (70 mg,89%) as yellow oil. MS (ESI): m/z=363.1 [M+H]⁺.

Example 565-(1-acryloylpiperidin-4-yl)-1-(4-phenoxyphenyl)-1H-pyrazole-3-carboxamide

To the solution of1-(4-phenoxyphenyl)-5-(piperidin-4-yl)-1H-pyrazole-3-carboxamidehydrochloride 12 (110 mg, 0.3 mmol), DIPEA (117 mg, 0.9 mmol) and CH₂Cl₂(10 mL) was added acryloyl chloride (28 mg, 0.3 mmol) dropwise and thenthe reaction mixture was stirred at 0° C. for 1 h. The mixture wasdiluted with CH₂Cl₂ (20 mL) and washed with saturated aqueous NaHCO₃solution (20 mL). The aqueous phase was reextracted with EtOAc (20 mL).The combined organic phase was dried over Na₂SO₄, concentrated in vacuoand purified by Prep-TLC developing with 20:1 CH₂C₂/MeOH to give thetitle compound (66 mg, 52%) as yellow oil. ¹H NMR (300 MHz, CD₃OD) δ7.52-7.37 (m, 4H), 7.24-7.06 (m, 5H), 6.84-6.68 (m, 2H), 6.21 (d, J=2.0Hz, 0.5H), 6.15 (d, J=2.0 Hz, 0.5H), 5.73 (dd, J=10.6, 2.0 Hz, 1H), 4.61(d, J=12.8 Hz, 1H), 4.15 (d, J=14.0 Hz, 1H), 3.04 (tt, J=8.0, 7.5 Hz,2H), 2.77-2.59 (m, 1H), 2.03-1.81 (m, 2H), 1.72-1.46 (m, 2H). MS (ESLmethod A): m % z=417.1 [M+H]¹, t_(R)=1.547 min. HPLC: 98.2% (214 nm),98.8% (254 nm).

methyl 2-bromo-4-fluorobenzoate (2)

To a mixture of 2-bromo-4-fluorobenzoic acid 1 (2.19 g, 10 mmol) in MeOH(20 mL) was added SOCl₂ (0.5 mL) dropwise at rt. The resulting mixturewas stirred at 60° C. for 10 h. The mixture was concentrated to give thetitle compound (2 g, 86%) as brown oil. MS (ESI): m/z=232.8 [M+H]⁺.

2-bromo-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid (4)

To a solution of methyl 2-bromo-4-fluorobenzoate 2 (1.8 g, 7.72 mmol) inDMSO (30 mL) was added tert-butyl piperazine-1-carboxylate 3 (1.726 g,9.27 mmol) and K₂CO₃ (4.26 g, 30.9 mmol). The mixture was stirred at120° C. for 5 h. When finished, the mixture was extracted with ethylacetate (2×50 mL), and washed with water (50 mL) and brine (2 k 50 mL).The organic layer was dried over Na₂SO₄, filtered and concentrated toget a residue which was purified by silica gel column chromatographyeluting with 10:1 PE/EA to get the title compound (1.1 g, 36%) as ayellow oil. MS (ESI): m/z=328.7 [M−55]⁺.

tert-butyl 4-(3-bromo-4-carbamoylphenyl)piperazine-1-carboxylate (5)

The title compound was obtained using a procedure analogous to theprocedure described in tert-butyl3-(5-carbamoyl-4-(4-phenoxyphenyl)thiazol-2-yl)pyrrolidine-1-carboxylate(see Scheme 31) as a yellow solid (0.8 g, 73%). MS (ESI): m/z=327.7[M−55]⁺.

tert-butyl4-(6-carbamoyl-4′-phenoxybiphenyl-3-yl)piperazine-1-carboxylate (6)

To a mixture of tert-butyl4-(3-bromo-4-carbamoylphenyl)piperazine-1-carboxylate 5 (192 mg, 0.5mmol), 4-phenoxyphenylboronic acid (102 mg, 0.5 mmol) and K₂CO₃ (207 mg,1.5 mmol) in dioxane/water (20/4 mL) were added Pd(dppf)₂Cl₂ (36.55 mg,0.05 mmol). The mixture was degassed with N₂ 3 times, then heated to100° C. and stirred for 16 h. After cooling to room temperature, themixture was added to ethyl acetate (30 mL), washed with water (2×20 mL)and brine (2×20 mL). The organic layer was dried over Na₂SO₄, filteredand concentrated to get a residue which was purified by silica gelcolumn chromatography eluting with 30:1 DCM/MeOH to get the titlecompound (50 mg, 21%) as a yellow solid. MS (ESI): m/z=473.8 [M+H]⁺

4′-phenoxy-5-(piperazin-1-yl)biphenyl-2-carboxamide hydrochloride (7)

The title compound was obtained using a procedure analogous to theprocedure described in1-(4-phenoxyphenyl)-5-(piperidin-4-yl)-1H-pyrazole-3-carboxamidehydrochloride (see Scheme 46) as a yellow solid (40 mg, 92%). MS (ESI):m/z=374.1 [M+H]⁺.

Example 57 5-(4-acryloylpiperazin-1-yl)-4′-phenoxybiphenyl-2-carboxamide

The title compound was obtained using a procedure analogous to theprocedure described in Example 1 as an off white solid (15 mg, 36%). ¹HNMR (400 MHz, DMSO) δ 7.52-7.30 (m, 6H), 7.25-6.93 (m, 7H), 6.91-6.82(m, 2H), 6.15 (d, J=16.7 Hz, 1H), 5.73 (d, J=9.9 Hz, 1H), 3.70 (d,J=12.0 Hz, 4H), 3.27 (s, 4H). MS (ESI, method A): m/z=428.1 [M+H]⁺,t_(R)=1.525 min. HPLC: 96.4% (214 nm), 99.3% (254 nm)

2-(4-benzoylphenyl)₆-chloronicotinamide (2)

To a solution of 4-phenoxyphenylboronic acid (650 mg, 2.88 mmol), K₂CO₃(1.08 g, 7.86 mmol) and 2,6-dichloronicotinamide (500 mg, 2.62 mmol) in1,4-dioxane (25 mL) and water (4 mL) was added Pd(dppf)Cl₂ (192 mg,0.262 mmol) under nitrogen atmosphere, and the mixture was degassed withnitrogen 6 times, then heated to 60° C. and stirred for 12 h undernitrogen atmosphere. After cooling to room temperature, the solution waspoured into water (50 mL), and then extracted with ethyl acetate (2×50mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated. The crude product was purified bycolumn chromatography, eluting with 80:1 dichloromethane/methanol toafford the title compound as a brown oil (868 mg, 98%). MS (ESI):m/z=336.9 [M+H]⁺.

tert-butyl4-(6-(4-benzoylphenyl)-5-carbamoylpyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(4)

To a solution of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(1.2 g, 3.87 mmol), K₂CO₃ (1.07 g, 7.74 mmol) and2-(4-benzoylphenyl)-6-chloronicotinamide 2 (868 mg, 2.58 mmol) in1,4-dioxane (24 mL) and water (3 mL) was added Pd(dppf)Cl₂ (188 mg,0.258 mmol) under nitrogen atmosphere, and the mixture was degassed withnitrogen 6 times, then heated to 90° C. and stirred for 12 h undernitrogen atmosphere. After cooling to room temperature, the solution waspoured into water (50 mL), and then extracted with ethyl acetate (3×40mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated. The crude product was purified bycolumn chromatography, eluting with 80:1 dichloromethane/methanol toafford the title compound as a brown oil (800 mg, 64%). MS (ESI):m/z=484.0 [M+H]⁺.

tert-butyl-4-(5-carbamoyl-6-(4-(hydroxy(phenyl)methyl)phenyl)pyridin-2-yl)piperidine-1-carboxylate(5)

To a solution of tert-butyl4-(6-(4-benzoylphenyl)-5-carbamoylpyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate4 (800 mg, 1.65 mmol) in MeOH (15 mL) was added Pd/C (150 mg) underhydrogen atmosphere, and the mixture was degassed with hydrogen 6 times,then stirred for 16 h at ambient temperature under hydrogen atmosphere.The solution was filtered and the filtrate was evaporated to providecrude product as a white solid (500 mg, 62%). MS (ESI): m/z=488.1[M+H]⁺.

2-(4-(hydroxy(phenyl)methyl)phenyl)-6-(piperidin-4-yl)nicotinamide (6)

To a solution of tert-butyl4-(5-carbamoyl-6-(4-(hydroxy(phenyl)methyl)phenyl)pyridin-2-yl)piperidine-1-carboxylate5 (500 mg, 1.03 mmol) in dry dichloromethane (5 mL) was added TFA (2mL), and the resulting mixture was stirred for 3 h at ambienttemperature. The solvent was removed and the residue was partitionedbetween saturated aqueous sodium bicarbonate (30 mL) and ethyl acetate(20 mL). The organic phase was separated, dried over anhydrous sodiumsulfate, filtered and concentrated to afford the title compound as awhite solid (350 mg, 88%). MS (ESI): m/z=388.1 [M+H]⁺.

Example 586-(1-acryloylpiperidin-4-yl)-2-(4-(hydroxy(phenyl)methyl)phenyl)nicotinamide

To a solution of 2-(4-(hydroxy(phenyl)methyl)phenyl)-6-(piperidin-4-yl)nicotinamide 6 (350 mg, 0.90 mmol) in DCM (10 mL) was added TEA (182 mg,1.8 mmol) and acryloyl chloride (90 mg, 0.99 mmol) at 0° C. The mixturewas stirred at 0° C. for 10 min. The solvent was removed and the residuewas purified by Prep-HPLC to afford the title compound (150 mg, 38%) aswhite solid. ¹H NMR (300 MHz, CDCl₃) δ 8.03 (d, J=7.9 Hz, 1H), 7.65 (d,J=7.1 Hz, 2H), 7.56-7.15 (m, 9H), 6.67-6.49 (m, 1H), 6.27 (d, J=16.6 Hz,1H), 5.88 (s, 1H), 5.68 (d, J=10.1 Hz, 1H), 5.52 (d, J=27.1 Hz, 2H),4.79-4.72 (m, 1H), 4.11-4.06 (m, 1H), 3.18-3.10 (m, 2H), 2.80-2.74 (m,1H), 2.08-1.98 (m, 2H), 1.78 (d, J=10.5 Hz, 2H). MS (ESI, method F):m/z=441.8 [M+H]⁺, t_(R)=1.268 min., HPLC: 100.0% (214 nm), 100.0% (254nm).

Example 59(E)-1-(1-(2-cyanobut-2-enoyl)azetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide

To a solution of1-(1-(2-cyanoacetyl)azetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide(150 mg, 0.37 mmol) and piperidine (3 drops) in AcOH (10 mL) was addedacetaldehyde (99 mg, 0.74 mmol), then stirred at 45° C. overnight. Afterthe reaction was completed, sat. NaOH was added to the solution topH=6-7. Then the solution was extracted with DCM (2×20 mL). The organiclayer was combined and concentrated under vacuum to dryness. The residuewas purified by Prep-HPLC (MeOH—H₂O=60-70, 0.1% FA) to afford the titlecompound (40 mg, 26%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.15(s, 1H), 7.79-7.68 (m, 1H), 7.62-7.54 (m, 2H), 7.43-7.34 (m, 2H),7.21-7.13 (m, 1H), 7.13-7.04 (m, 4H), 5.62 (s, 2H), 5.26-5.10 (m, 1H),5.08-4.79 (m, 2H), 4.71-4.51 (m, 2H), 3.51-3.36 (m, 1H), 2.26-2.16 (m,2H). MS (ESL Method A): m/z=428.1 [M+H]⁺, t_(R)=1.438 min. HPLC: 98.4%(214 nm), 98.4% (254 nm).

8-(4-bromophenoxy)-1,4-dioxaspiro[4.5]decane (3)

The title compound was obtained using a procedure analogous to theprocedure described in 1-bromo-4-(cyclohexyloxy)benzene (see Scheme 17)as colorless oil (0.272 g, 87%).

4-(4-bromophenoxy)cyclohexanone (4)

A solution of 8-(4-bromophenoxy)-1,4-dioxaspiro[4.5]decane 3 (0.272 g,0.87 mmol) in THF (5 mL) was treated with HCl (1 N, 5 mL) at 50° C. for1 h. Then the mixture was neutralized with NaHCO₃ and extracted withEtOAc (5 mL×3). The combined organic phase was dried over Na₂SO₄,filtered and concentrated. The residue was purified by silica gel columnchromatography eluting with 5:1 petroleum ether/EtOAc to give the titlecompound (147 mg, 63%) as white solid. ¹H NMR (400 MHz, CDCl₃) δ7.46-7.37 (m, 2H), 6.91-6.83 (m, 2H), 4.68 (s, 1H), 2.75-2.64 (m, 2H),2.43-2.25 (m, 4H), 2.15-2.08 (s, 2H).

1-bromo-4-((4,4-difluorocyclohexyl)oxy)benzene (5)

To the solution of 4-(4-bromophenoxy)cyclohexanone 4 (0.538 g, 2.0 mmol)in dry DCM (5 mL) was added a solution of DAST (0.654 g, 4.0 mmol) indry DCM (5 mL) at 0° C. and the resulting mixture was stirred at rt for4 h. The reaction was quenched by ice water (5 mL), basified withsaturated NaHCO₃ to pH=8 and extracted with EtOAc (10 mL×3). Thecombined organic phase was dried over Na₂SO₄, filtered and concentrated.The residue was purified by silica gel column chromatography elutingwith 10:1 petroleum ether/EtOAc to afford the title compound (0.547 g,94%) as yellow oil.

2-(4-((4,4-difluorocyclohexyl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(6)

The mixture of 1-bromo-4-((4,4-difluorocyclohexyl)oxy)benzene 5 (0.328g, 1.13 mmol), bis(pinacolato)diboron (0.429 g, 1.69 mmol), Pd(dppf)Cl₂(0.168 g, 0.23 mmol), KOAc (0.323 g, 3.29 mmol) and dry dioxane (3 mL)was stirred at 100° C. for 3 h. After cooled to rt, the mixture waspoured into water (10 mL) and extracted with EtOAc (15 mL×3). Thecombined organic phase was dried over Na₂SO₄, filtered and concentrated.The residue was purified by silica gel column chromatography elutingwith PE to afford the title compound (0.258 g, 68%) as a white solid.

2-(4-((4,4-difluorocyclohexyl)oxy)phenyl)-6-(piperazin-1-yl)nicotinamide(8)

The title compound was obtained using a procedure analogous to theprocedure described in 6-(3-nitrophenyl)-2-(4-phenoxyphenyl)nicotinamide(see Scheme 1) as white solid (0.10 g, 31%). MS (ESI): m/z=417.1 [M+H]⁺.

Example 606-(4-acryloylpiperazin-1-yl)-2-(4-((4,4-difluorocyclohexyl)oxy)phenyl)nicotinamide

The title compound was obtained using a procedure analogous to theprocedure described in Example 1 as white solid (6 mg, 11%). ¹H NMR (400MHz, DMSO-d6) δ 7.88 (d, J=8.7 Hz, 2H), 7.73 (d, J=8.6 Hz, 2H), 7.68 (d,J=8.7 Hz, 1H), 7.59 (s, 1H), 7.26 (s, 1H), 7.21-7.14 (m, 4H), 6.86 (dd,J=17.8, 9.3 Hz, 2H), 6.16 (dd, J=16.7, 2.2 Hz, 1H), 5.73 (dd, J=10.4,2.2 Hz, 1H), 3.66-3.67 (m, 8H). MS (ESI, method A): m/z=471.2 [M+H]⁺,t_(R)=1.753 (min). HPLC: 99.2% (214 nm), 99.2% (254 nm).

2,6-dichloronicotinamide (2)

The title compound was synthesized using a procedure analogous to theprocedure described in 2,6-dichloronicotinamide (see Scheme 51) (9.5 g,81%) as a brown solid. MS (ESI): m/z=191.0 [M+H]⁺.

methyl 4-(3-carbamoyl-6-chloropyridin-2-yl)benzoate (4)

To a solution of 2,6-dichloronicotinamide 2 (1.91 g, 10.0 mmol),4-(methoxycarbonyl)phenylboronic acid 3 (1.8 g, 10.0 mmol) andPd(dppf)Cl₂ (816 mg, 1.0 mmol) in DME/H₂O (20 mL/2 mL) was added Cs₂CO₃(6.5 g, 20.0 mmol). The resulting solution was degassed with N₂ 6 timesand stirred overnight at 90° C. under N₂ protection. After the reactionwas completed, the solution was concentrated, diluted with ethyl acetate(30 mL) and washed with water (2×20 mL) and brine (2×20 mL). The organiclayer was dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel column diluted with100:1 to 60:1 DCM/MeOH to afford the title compound (1.95 g, 67%) as awhite solid. MS (ESI): m/z=291.1 [M+H]⁺.

tert-butyl-4-(5-carbamoyl-6-(4-(methoxycarbonyl)phenyl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(6)

To a solution of methyl 4-(3-carbamoyl-6-chloropyridin-2-yl)benzoate 4(170 mg, 0.59 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate5 (200 mg, 0.65 mmol) and Pd(dppf)Cl₂ (50 mg, 0.06 mmol) in DME/H₂O (20mL/2 mL) was added Cs₂CO₃ (390 mg, 1.2 mmol), the resulting solution wasdegassed with N₂ 6 times and stirred overnight at 90° C. under N₂. Afterthe reaction was completed, the solution was concentrated, diluted withethyl acetate (30 mL) and washed with water (2×20 mL) and brine (2×20mL). The organic layer was dried over anhydrous sodium sulfate, filteredand concentrated. The residue was purified by silica gel column dilutedwith 50:1 to 10:1 DCM/MeOH to afford the title compound (145 mg, 56%) asbrown oil. MS (ESI): m/z=438.2 [M+H]⁺.

tert-butyl-4-(5-carbamoyl-6-(4-(methoxycarbonyl)phenyl)pyridin-2-yl)piperidine-1-carboxylate(7)

To a solution of tert-butyl4-(5-carbamoyl-6-(4-(methoxycarbonyl)phenyl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate6 (145 mg, 0.33 mmol) in MeOH (10 mL) was added Pd/C (15 mg) anddegassed with H₂ 6 times and stirred overnight at rt under H₂. After thereaction was completed, the solution was filtered and the filtrate wasconcentrated to afford the title compound (100 mg, 69%) as brown oil. MS(ESI): m/z=440.2 [M+H]⁺.

4-(6-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-carbamoylpyridin-2-yl)benzoicacid (8)

To a solution of tert-butyl4-(5-carbamoyl-6-(4-(methoxycarbonyl)phenyl)pyridin-2-yl)piperidine-1-carboxylate7 (460 mg, 1.05 mmol) in THF/H₂O (20 mL/2 mL) was added LiOH (84 mg, 2.1mmol), the resulting solution was stirred overnight at rt. After thereaction was complete, the solution was concentrated, added water (10mL) and acidified with HCl (conc., 1 mL) to pH=5-6, diluted with ethylacetate (30 mL) and washed with water (2×20 mL) and brine (2×20 mL). Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated to afford the title compound (390 mg, 87%) as a yellowsolid. MS (ESI): m/z=426.2 [M+H]⁺.

tert-butyl-4-(5-carbamoyl-6-(4-(phenylcarbamoyl)phenyl)pyridin-2-yl)piperidine-1-carboxylate(9)

To a solution of4-(6-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-carbamoylpyridin-2-yl)benzoicacid 8 (390 mg, 0.917 mmol), aniline (102 mg, 1.101 mmol) and HATU (418mg, 1.101 mmol) in dry DMF (10 mL) was added DIEA (355 mg, 2.751 mmol),the resulting solution was stirred overnight at rt. The mixture wasdiluted with ethyl acetate (30 mL), and washed with water (2×20 mL) andbrine (2×20 mL). The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by Prep-TLCwith 20:1 DCM/MeOH to get the title compound (120 mg, 27%) as a yellowsolid. MS (ESI): m/z=501.2 [M+H]⁺.

2-(4-(phenylcarbamoyl)phenyl)-6-(piperidin-4-yl)nicotinamide (10)

To a solution of tert-butyl4-(5-carbamoyl-6-(4-(phenylcarbamoyl)phenyl)pyridin-2-yl)piperidine-1-carboxylate9 (120 mg, 0.24 mmol) in dry DCM (10 mL) was added TFA (3 mL), theresulting solution was stirred overnight at it. The mixture was washedwith NaHCO₃/H₂O (3×20 mL) and brine (3×20 mL). The organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated. Theresidue was concentrated to get the title compound (100 mg, 99%) as ayellow solid. MS (ESI): m/z=401.2 [M+H]⁺.

Example 616-(1-acryloylpiperidin-4-yl)-2-(4-(phenylcarbamoyl)phenyl)nicotinamide

To a solution of 2-(4-(phenylcarbamoyl)phenyl)-6-(piperidin-4-yl)nicotinamide 10 (100 mg, 0.24 mmol)in dry DCM (15 mL) was added DIEA (95 mg, 0.72 mmol) and acryloylchloride (35 mg, 0.36 mmol) at 0° C., and the resulting solution wasstirred at 0° C. for 10 min. Water (10 mL) was added to quench thereaction. The mixture was diluted with DCM (20 mL), and washed withwater (2×20 mL) and brine (2×20 mL). The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated. The residue waspurified by Prep-HPLC (ACN-H₂O=30-90, 0.1% FA) to afford the titlecompound (31 mg, 29%) as a white solid. ¹H NMR (300 MHz, CDCl₃) 8.59 (s,1H), 8.04-7.58 (m, 3H), 7.75-7.54 (m, 4H), 7.37-7.27 (m, 2H), 7.21-7.08(m, 2H), 6.65-6.49 (m, 1H), 6.29-6.10 (m, 3H), 5.74-5.63 (m, 1H),4.79-4.63 (m, 1H), 4.17-3.99 (m, 1H), 3.27-2.96 (m, 2H), 2.83-2.66 (m,1H), 2.07-1.88 (m, 2H), 1.83-1.60 (m, 2H). MS (ESI): m/z=455.2 [M+H]⁺,t_(R)=1.316 min. HPLC: 95.3% (214 nm), 93.0% (254 nm).

Example 622-(4-phenoxyphenyl)-6-(4-(vinylsulfonyl)piperazin-1-yl)nicotinamide

To a solution of 2-(4-phenoxyphenyl)-6-(piperazin-1-yl)nicotinamide 1(200 mg, 0.53 mmol) in DCM (8 mL) was added TEA (161 mg, 1.59 mmol) and2-chloroethanesulfonyl chloride (131 mg, 0.80 mmol) at rt. The mixturewas stirred at rt for 1 h. The solution was poured into water (50 mL),and then extracted with CH₂Cl₂ (2×50 mL). The combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentrated, andthe residue was purified by Prep-TLC eluting with 100:1 DCM/MeOH toafford the title compound (17 mg, 6.9%) as a white solid. ¹H NMR (300MHz, CDCl₃) δ 8.01 (d, J=8.8 Hz, 1H), 7.59 (d, J=8.6 Hz, 2H), 7.43-7.30(m, 2H), 7.15 (t, J=7.4 Hz, 1H), 7.09-7.01 (m, 4H), 6.64 (d, J=8.8 Hz,1H), 6.42 (dd, J=16.6, 9.7 Hz, 1H), 6.26 (d, J=16.5 Hz, 1H), 6.06 (d,J=9.7 Hz, 1H), 5.46 (br, 1H), 5.28 (br, 1H), 3.87-3.75 (m, 4H),3.32-3.18 (m, 4H). MS (ESI, method F): m/z=465.1.0 [M+H]⁺, t_(R)=1.546min., HPLC: 99.5% (214 nm), 98.3% (254 nm).

Example 632-(4-phenoxyphenyl)-6-(1-(vinylsulfonyl)piperidin-4-yl)nicotinamide

To a solution of 2-(4-phenoxyphenyl)-6-(piperidin-4-yl)nicotinamide 1(200 mg, 0.54 mmol) in DCM (8 mL) was added TEA (164 mg, 1.62 mmol) and2-chloroethanesulfonyl chloride (131 mg, 0.80 mmol) at rt. The mixturewas stirred at rt for 1 h. The solution was poured into water (50 mL),and then extracted with ethyl acetate (2×50 mL). The combined organiclayers were dried over anhydrous sodium sulfate, filtered andconcentrated, and the residue was purified by Prep-HPLC to afford thetitle compound (40 mg, 16%) as a white solid. ¹H NMR (300 MHz, CDCl₃)8.03 (d, J=8.0 Hz, 1H), 7.71-7.61 (m, 2H), 7.43-7.31 (m, 2H), 7.17 (dd,J=15.6, 7.8 Hz, 2H), 7.10-7.01 (m, 4H), 6.46 (dd, J=16.6, 9.8 Hz, 1H),6.26 (d, J=16.6 Hz, 1H), 6.04 (d, J=9.9 Hz, 1H), 5.60 (b, 1H), 5.41 (b,1H), 3.94-3.82 (m, 2H), 2.97-2.86 (m, 1H), 2.80-2.71 (m, 2H), 2.11-1.92(m, 4H). MS (ESI, method F): m/z=464.0 [M+H]⁺, t_(R)=1.566 min., HPLC:99.3% (214 nm), 100.0% (254 nm).

The following examples can be synthesized according to methodsreferenced below and utilizing ordinary skill in the art. These examplesare believed to be useful as inhibitors of BTK based on the biologicalactivities of the compounds described above.

Example 641-(1-acryloylpiperidin-3-(4-(phenylcarbamoyl)phenyl)-1H-pyrazole-4-carboxamide

The title compound may be obtained using a procedure analogous to theprocedures described in the General Scheme and Example 15.

Example 651-(1-acryloylpiperidin-3-yl)-3-(4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-1H-pyrazole-4-carboxamide

The title compound may be obtained using a procedure analogous to theprocedures described in the General Scheme and Example 15.

Example 66 6-(4-acrylamidophenyl)-2-(4-(phenylcarbamoyl)phenyl)nicotinamide

The title compound may be obtained using a procedure analogous to theprocedures described in the General Scheme and Example 16.

Example 676-(4-acrylamidophenyl)-2-(4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)nicotinamide

The title compound may be obtained using a procedure analogous to theprocedures described in the General Scheme and Example 16.

Example 681-(1-acryloylpiperidin-3-yl)-3-(4-(hydroxy(phenyl)methyl)phenyl)-1H-pyrazole-4-carboxamide

The title compound may be obtained using a procedure analogous to theprocedures described in the General Scheme and Examples 15 and 58.

Example 691-(1-acryloylpiperidin-3-yl)-3-(4-(methyl(phenyl)amino)phenyl)-1H-pyrazole-4-carboxamide

The title compound may be obtained using a procedure analogous to theprocedures described in the General Scheme and Example 15.

Example 706-(4-acrylamidophenyl)-2-(4-(1-hydroxy-1-phenylethyl)phenyl)nicotinamide

The title compound may be obtained using a procedure analogous to theprocedures described in the General Scheme and Examples 16 and 58.

Example 716-(4-acrylamidophenyl)-2-(4-(difluoro(phenyl)methyl)phenyl)nicotinamide

The title compound may be obtained using a procedure analogous to theprocedures described in the General Scheme and Example 16.

Example 721-(1-acryloylpiperidin-3-yl)-3-(4-(phenylsulfonyl)phenyl)-1H-pyrazole-4-carboxamide

The title compound may be obtained using a procedure analogous to theprocedures described in the General Scheme and Example 15.

Example 73 6-(4-acrylamidophenyl)-2-(4-(phenylsulfonyl)phenyl)nicotinamide

The title compound may be obtained using a procedure analogous to theprocedures described in the General Scheme and Example 16.

ethyl 5-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate (2)

The title compound was obtained using a procedure analogous to theprocedure described in ethyl3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate (see Scheme 23) as yellowoil (0.3 g, 97%). MS (ESI): m/z=308.8 [M+H]⁺.

ethyl 1-cyclopentyl-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate (4)

To a solution of ethyl 5-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate 2(150 mg, 0.486 mmol) in DMF (10 mL) was added bromocyclopentane 3 (87mg, 0.584 mmol) and Cs₂CO₃ (475.5 mg, 1.46 mmol). The mixture wasstirred at 100° C. for 3 h. After finished, the mixture was extractedwith ethyl acetate (2×30 mL), and washed with water (2×10 mL) and brine(3×10 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated to give the title compound (0.13 g, 71%) as yellow oil. MS(ESI): m/z=376.9 [M+H]⁺

1-cyclopentyl-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylic acid (5)

The title compound was obtained using a procedure analogous to theprocedure described in5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-(4-phenoxyphenyl)-1H-pyrazole-3-carboxylicacid (see Scheme 46) as yellow oil (0.12 g, 100%). MS (ESI): m/z=348.8[M+H]⁺.

Analog 1 1-cyclopentyl-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide

The title compound was obtained using a procedure analogous to theprocedure described in tert-butyl3-(5-carbamoyl-4-(4-phenoxyphenyl)thiazol-2-yl)pyrrolidine-1-carboxylate(see Scheme 31) as an off white solid (70 mg, 59%). ¹H NMR (300 MHz,DMSO) δ 8.23 (s, 1H), 7.79 (d, J=8.5 Hz, 2H), 7.41 (t, J=7.0 Hz, 3H),7.15 (t, J=7.1 Hz, 1H), 7.05 (d, J=7.6 Hz, 2H), 7.00 (s, 2H), 6.98 (d,J=1.4 Hz, 1H), 4.78-4.62 (m, 1H), 2.19-1.55 (m, 8H). MS (ESI, method F):m/z=347.9 [M+H]¹, t_(R)=1.589 (min). HPLC: 97.6% (214 nm), 98.0% (254nm).

cyclopentanecarboxamide (2)

To a mixture of cyclopentanecarboxylic acid 1 (2.85 g, 25 mmol) and DMF(3 drops) in DCM (60 mL) was added (COCl)₂ (3.2 g, 25 mmol) dropwisecarefully at 0° C. under N₂. The resulting mixture was stirred at rt for2 h, then NH₄OH (5 mL) was added dropwise to this mixture at 0° C. Afterthe addition, the mixture was stirred at rt for another 1 h, which wasdiluted with DCM (50 mL). It was washed with water (50 mL), brine, driedover sodium sulfate, filtered and concentrated. This resulted in thetitle compound (1.8 g, 64%0) as white solid. MS (ESI): m/z=114.8 [M+H]⁺.

cyclopentanecarbothioamide (3)

A mixture of cyclopentanecarboxamide 2 (1.8 g, 15.9 mmol) and lawesson'sreagent (3.2 g, 8.0 mmol) in toluene (40 mL) was stirred at 80° C. for 2h under N₂ atmosphere. It was quenched with sat. NaHCO₃ (50 mL). whichwas extracted with EA (2×40 mL). The organic layers were combined,washed with brine, dried over sodium sulfate, filtered and concentrated.The residue was applied onto silica gel column eluting with 3:1 PE/EA toget the title compound (0.25 g, 12%) as yellow solid. MS (ESI):m/z=130.1 [M+H−56]⁺.

ethyl 2-cyclopentyl-4-(4-phenoxyphenyl)thiazole-5-carboxylate (4)

A mixture of cyclopentanecarbothioamide 3 (150 mg, 1.16 mmol) and ethyl2-bromo-3-oxo-3-(4-phenoxyphenyl)propanoate (422 mg, 1.16 mmol) in EtOH(15 mL) was refluxed for 2 h. The volatile phase was removed underreduced pressure. The residue was dissolved in EA (50 mL), which waswashed with sat. NaHCO₃ (30 mL), brine, dried over sodium sulfate,filtered and concentrated. The residue was applied onto silica gelcolumn eluting with 4:1 PE/EA to get the title compound (200 mg, 43%) aspale yellow oil. MS (ESI): m/z=394.1 [M+H]⁺.

2-cyclopentyl-4-(4-phenoxyphenyl)thiazole-5-carboxylic acid (5)

The title compound was obtained using a procedure analogous to theprocedure described in5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4′-phenoxybiphenyl-2-carboxylicacid (see Scheme 45) as pale yellow solid (190 mg, 99%). MS (ESI):m/z=366.1 [M+H]⁺.

Analog 2 2-cyclopentyl-4-(4-phenoxyphenyl)thiazole-5-carboxamide

The title compound was obtained using a procedure analogous to theprocedure described in tert-butyl4-(6-carbamoyl-4′-phenoxybiphenyl-3-yl)piperidine-1-carboxylate (seeScheme 45) as white solid (70 mg, 38%). ¹H NMR (300 MHz, CDCl₃) δ7.66-7.56 (m, 2H), 7.43-7.33 (m, 2H), 7.17 (t, J=7.4 Hz, 1H), 7.12-7.00(m, 4H), 5.73 (brs, 2H), 3.52-3.35 (m, 1H), 2.32-2.16 (m, 2H), 1.90-1.77(m, 4H), 1.76-1.66 (m, 2H). MS (ESI, method A): m/z=365.1 [M+H]¹,t_(R)=1.780 min. HPLC: 97% (214 nm), 96% (254 nm).

Analytical Conditions

Unless otherwise noted, all solvents, chemicals, and reagents wereobtained commercially and used without purification. The 1H-NMR spectrawere obtained in CDCl₃, DMSO-d₆, CD₃OD, or acetone-d₆ at 25° C. at 300MHz or 400 MHz on an OXFORD (Varian) with chemical shift (δ, ppm)reported relative to TMS as an internal standard. HPLC-MS chromatogramsand spectra were obtained with an Agilent 1200-6110 system. Prep-HPLCinstruments were Gilson GX-281 (Gilson) and P230 Preparative GradientSystem (Gradient: 95% water, 5% acetonitrile, 30-50 min gradient to 25%water, 75% acetonitrile). The microwave instrument was a CEM DiscoverSP.

Biological Properties: IC₅₀ Determination of BTK Inhibitors in ADP-GloKinase Biochemical Assay

The activity of the Examples and Analogs described herein, as inhibitorsof BTK are demonstrated and confirmed by pharmacological in vitroassays. Activity possessed by the compounds may be demonstrated in vivo.Those skilled in the art will appreciate that a variety of assay formatsmay be used to determine the activity of the compounds described herein.

Materials:

ADP-Glo™ Kinase Assay (cat. V9102, 10000 tests), components:

-   -   1×50 ml ADP-Glo™ Reagent,    -   1×100 ml Kinase Detection Buffer,    -   1× Kinase Detection Substrate (Lyophilized),    -   1×5 ml Ultra Pure ATP, 10 mM    -   1×5 ml ADP, 10 mM        Reagents and Plate:

Tris.Hcl (Sigma cat. 154563), MgCl₂ (Sigma cat.M1028), MnCl₂ (Sigma,M3634), BSA (Sigma cat. 05470), BTK Substrate (Signalchem, P61-58), DTT(Sigma, D0632), DMSO (Sigma, S5879), BTK enzyme. (1.5 mg/ml, purity 75%,90 ng/ul, made in house). 384 well assay plate (cat. 3674).

Assay Conditions:

-   -   Enzyme concentration: 8 ng/5 ul.    -   ATP concentration: 50 uM    -   Substrate (peptide) concentration: 0.2 mg/ml.    -   Reaction buffer composition: 40 mM Tris-HCl pH7.5, 10 mM MgCl₂,        2 mM MnCl₂, 0.1 mg/mL BSA, 0.05 mM DTT.    -   Test compound concentration: DMSO≤0.5%.        Methods:        Compound Dosage Gradient Solution Preparation:

A 3-fold serial dilution of test compound was made for 10 gradientpoints (100, 33.33, 11.11, 3.70, 1.23, 0.41, 0.14, 0.046, 0.015, 0.005uM) in 100% DMSO. The intermediate dilution was done by adding 2 ul ofdiluted compound into 78 ul of assay buffer (containing 40 mM Tris.Hcl,pH 7.5 10 mM MgCl₂, 2 mM MnCl, 0.1 mg/mL BSA, 0.05 mM DTT), making thefinal compound concentration (1000, 333.33, 111.11, 37.04, 12.35, 4.12,1.37, 0.46, 0.15, 0.05 nM) and DMSO concentration 0.5% percentage.

ADP-Glo Kinase Assay Protocol for BTK Inhibitors Testing:

1× and 2× assay buffer were made at first. BTK kinase was diluted with1× assay buffer but substrate was diluted with 2× assay buffer. 1 ul ofdiluted compound was transferred into 384-well assay plate, and then 2.0ul of enzyme solution was added, and spun at 2000 rpm for 1 min. Thismixture was incubated at 24° C. for 30 mins. 2 ul of peptidesubstrate/ATP mixture was added into the assay plate to start thereaction. The mixture was mixed thoroughly and then the 384-well platewas spun and incubated at 24° C. for 60 mins. 5.0 ul of ADP-Glo Reagentwas added to stop the kinase activity and deplete the ATP unconsumed,and the plate was mixed thoroughly and incubated at 24° C. for 40 min.Then, 10.0 ul of Kinase Detection reagent was added, and the plate wascentrifuged and then kept at 24° C. for 30 min. The luminescence signalwas read on Envision.

Data Analysis:

% inhibition of compounds at each different concentration is calculatedfrom Equation (1):% inhibition=100−100*(Signal−low control)/(High control−lowcontrol)  Equation(1)

IC₅₀ values of compounds were calculated from a 4-parameter fit usingEquation (2):Y=Bottom+(TOP−Bottom)/(1+((C/X)^hillslope))  Equation (2)

In Equation 2, Y represents % inhibition, X is the log value of the testcompound concentration. IC₅₀ was the concentration of compound wherehalf of maximal inhibition was achieved.

All data was analyzed with IDBS XLfit5 software (ID Business SolutionsLtd., UK). The IC₅₀ data is summarized in Table 1.

TABLE 1 IC₅₀ BTK Activity Values For Examples 1-63 IC₅₀ (nM) Examples≥1000 2, 4, 14, 27, 30, 33, 50, 53, 56 ≥500 9, 24, 31 ≤1000 ≥0 1, 3, 5,6, 7, 8, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, ≤500 21, 22, 23, 25,26, 28, 29, 32, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,48, 49, 51, 52, 54, 55, 57, 58, 59, 60, 61, 62, 63

Table 2 provides a comparison of Examples 3 and 5 to Analogs 1 and 2 interms of in vitro BTK potency. Examples 3 and 5 demonstrate about a 100×improvement in potency over Analogs 1 and 2 when compared inhead-to-head assays.

TABLE 2 Comparison of Examples 3 and 5 to Analogs 1 and 2 Target Example3 Example 5 Analog 1 Analog 2 BTK 4.4 4.7 347.4 364.5

Examples 3 and 5 also demonstrate from 10×-100× differences in potencybetween BTK and Src and are thus selective for BTK over Src.

Furthermore, selectivity of Examples 3 and 5 was determined. Table 3provides in vitro biochemical data demonstrating that Examples 3 and 5are selective for BTK over Src.

TABLE 3 Selectivity Data for Examples 3 and 5 Example 3 Example 5 Target% Inhibition @ 1000 nM % Inhibition @ 1000 nM BTK 99.35 99.7 SRC 23  33   Fold >100x   >100x   Difference

To obtain the data provided in Table 3, kinase-tagged T7 phage strainswere grown in parallel in 24-well blocks in an E. coli host derived fromthe BL21 strain. E. coli were grown to log-phase and infected with T7phage from a frozen stock (multiplicity of infection=0.4) and incubatedwith shaking at 32° C. until lysis (90-150 minutes). The lysates werecentrifuged (6,000×g) and filtered (0.2 μm) to remove cell debris. Theremaining kinases were produced in HEK-293 cells and subsequently taggedwith DNA for qPCR detection. Streptavidin-coated magnetic beads weretreated with biotinylated small molecule ligands for 30 minutes at roomtemperature to generate affinity resins for kinase assays. The ligandedbeads were blocked with excess biotin and washed with blocking buffer(SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unboundligand and to reduce nonspecific phage binding. Binding reactions wereassembled by combining kinases, liganded affinity beads, and testcompounds in 1× binding buffer (20% SeaBlock, 0.17×PBS, 0.05% Tween 20,6 mM DTT).

Example compounds were prepared as 40× stocks in 100% DMSO and directlydiluted into the assay. All reactions were performed in polypropylene384-well plates in a final volume of 0.04 ml. The assay plates wereincubated at room temperature with shaking for 1 hour and the affinitybeads were washed with wash buffer (1×PBS, 0.05% Tween 20). The beadswere then re-suspended in elution buffer (1×PBS, 0.05% Tween 20, 0.5 μMnon-biotinylated affinity ligand) and incubated at room temperature withshaking for 30 minutes. The kinase concentration in the eluates wasmeasured by qPCR.

The compound(s) were screened at 1000 nM, and results for primary screenbinding interactions are provided in Table 3 as “% Ctrl”, where lowernumbers indicate stronger hits. The % Ctrl is calculated according toEquation (1), below:

$\begin{matrix}{\left( \frac{{{test}\mspace{14mu}{compound}\mspace{14mu}{signal}} - {{positive}\mspace{14mu}{control}\mspace{14mu}{signal}}}{{{negative}\mspace{14mu}{control}\mspace{14mu}{signal}} - {{positive}\mspace{14mu}{control}\mspace{14mu}{signal}}} \right) \times 100} & (1)\end{matrix}$

Where:

-   -   test compound=Example    -   negative control=DMSO (100% Ctrl)    -   positive control=control compound (0% Ctrl)

Additional biological selectivity data for Examples 3 and 5 against eachmember of the SRC family of protein kinases as well as EGFR are providedin Table 4, below. The data in Table 4 was obtained using the sameprocedure as described above with respect to the data in Table 3.

TABLE 4 Selectivity Data for Examples 3 and 5 Example 3 Example 5 Target% Inhibition @ 1000 nM % Inhibition @ 1000 nM BLK 51 46 EGFR 20 23 FGR 00 FYN 0 5 HCK 0 21 LCK 11 0 LYN 3 7 YES 8 6Compositions:

The present invention includes pharmaceutical compositions comprising acompound or pharmaceutically acceptable salt thereof of the invention,which is formulated for a desired mode of administration with or withoutone or more pharmaceutically acceptable and useful carriers.

The compounds can also be included in pharmaceutical compositions incombination with one or more other therapeutically active compounds.

The pharmaceutical compositions of the invention comprise a compound ofthe invention (or a pharmaceutically acceptable salt thereof) as anactive ingredient, optional pharmaceutically acceptable carrier(s) andoptionally other therapeutic ingredients or adjuvants. The compositionsinclude compositions suitable for oral, rectal, topical, and parenteral(including subcutaneous, intramuscular, and intravenous) administration,although the most suitable route in any given case will depend on theparticular host, and nature and severity of the conditions for which theactive ingredient is being administered. The pharmaceutical compositionscan be conveniently presented in unit dosage form and prepared by any ofthe methods well known in the art of pharmacy.

Compounds of the invention can be combined as the active ingredient inintimate admixture with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques. The carrier can takea wide variety of forms depending on the form of preparation desired foradministration, e.g., oral or parenteral (including intravenous). Thus,the pharmaceutical compositions of the invention can be presented asdiscrete units suitable for oral administration such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient. Further, the compositions can be presented as a powder, asgranules, as a solution, as a suspension in an aqueous liquid, as anon-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oilliquid emulsion. In addition to the common dosage forms set out above,the compound represented by Formula I, or a pharmaceutically acceptablesalt thereof, can also be administered by controlled release meansand/or delivery devices. The compositions can be prepared by any of themethods of pharmacy. In general, such methods include a step of bringinginto association the active ingredient with the carrier that constitutesone or more necessary ingredients. In general, the compositions areprepared by uniformly and intimately admixing the active ingredient withliquid carriers or finely divided solid carriers or both. The productcan then be conveniently shaped into the desired presentation.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

A tablet containing the composition of this invention can be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets can be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets can be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.05 mg to about 5 g of the activeingredient and each cachet or capsule preferably containing from about0.05 mg to about 5 g of the active ingredient.

A formulation intended for the oral administration to humans may containfrom about 0.5 mg to about 5 g of active agent, compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95 percent of the total composition. Unit dosageforms will generally contain between from about 1 mg to about 2 g of theactive ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

Compounds of the invention can be provided for formulation at highpurity, for example at least about 90%, 95%, or 98% pure by weight.

Pharmaceutical compositions of the invention suitable for parenteraladministration may be prepared as solutions or suspensions of the activecompounds in water. A suitable surfactant can be included such as, forexample, hydroxypropylcellulose. Dispersions can also be prepared inglycerol, liquid polyethylene glycols, and mixtures thereof in oils.Further, a preservative can be included to prevent the detrimentalgrowth of microorganisms.

Pharmaceutical compositions of the invention suitable for injectable useinclude sterile aqueous solutions or dispersions. Furthermore, thecompositions can be in the form of sterile powders for theextemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the invention can be in a form suitablefor topical use such as, for example, an aerosol, cream, ointment,lotion, dusting powder, or the like. Further, the compositions can be ina form suitable for use in transdermal devices. These formulations maybe prepared, utilizing a compound represented by Formula I of thisinvention, or a pharmaceutically acceptable salt thereof, viaconventional processing methods. As an example, a cream or ointment isprepared by admixing hydrophilic material and water, together with about5 wt % to about 10 wt % of the compound, to produce a cream or ointmenthaving a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in molds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient.

Compositions containing a compound described by Formula I, orpharmaceutically acceptable salts thereof, may also be prepared inpowder or liquid concentrate form.

Uses:

Compounds of the present invention inhibit the activity of BTK inanimals, including humans, and are useful in the treatment and/orprevention of various diseases and conditions such as cancer,inflammation, fibrotic diseases, and autoimmune disease which arecaused, mediated and/or propagated by BTK. In particular, compounds ofthe invention, and compositions thereof, are inhibitors of BTK, and areuseful in treating conditions modulated, at least in part, by BTK.

In some aspects, the invention includes a method of treating cancercomprising administering to a mammal in need thereof a therapeuticallyeffective amount of a compound or salt of the invention.

In some aspects, the invention includes a method of treating a cancermediated at least in part by BTK comprising administering to a mammal inneed thereof a therapeutically effective amount of a compound or salt ofFormula I.

In some aspects, the invention includes a method of treating or a methodof manufacturing a medicament for treating a cancer, such as thosedescribed herein, which is mediated at least in part by BTK, comprisingadministering to a mammal in need thereof a therapeutically effectiveamount of a compound or salt of the invention.

In some aspects, the invention includes a method of treating lymphocytehoming and inflammation mediated at least in part by BTK comprisingadministering to a mammal in need thereof a therapeutically effectiveamount of a compound or salt of Formula I.

In some aspects, the invention includes a method of treating or a methodof manufacturing a medicament for treating lymphocyte homing andinflammation, such as those described herein, which is mediated at leastin part by BTK, comprising administering to a mammal in need thereof atherapeutically effective amount of a compound or salt of the invention.

In some aspects, the invention includes a method of treating neuropathicpain comprising administering to a mammal in need thereof atherapeutically effective amount of a compound or salt of the invention.

In some aspects, the invention includes a method of treating neuropathicpain mediated at least in part by BTK comprising administering to amammal in need thereof a therapeutically effective amount of a compoundor salt of Formula I.

In some aspects, the invention includes a method of treating or a methodof manufacturing a medicament for treating neuropathic pain, such asthose described herein, which is mediated at least in part by BTK,comprising administering to a mammal in need thereof a therapeuticallyeffective amount of a compound or salt of the invention.

In some aspects, the invention includes a method of treating fibroticdiseases comprising administering to a mammal in need thereof atherapeutically effective amount of a compound or salt of the invention.

In some aspects, the invention includes a method of treating fibroticdiseases mediated at least in part by BTK comprising administering to amammal in need thereof a therapeutically effective amount of a compoundor salt of Formula I.

In some aspects, the invention includes a method of treating or a methodof manufacturing a medicament for treating a fibrotic disease, such asthose described herein, which is mediated at least in part by BTK,comprising administering to a mammal in need thereof a therapeuticallyeffective amount of a compound or salt of the invention.

In some aspects, the invention includes a method of treating thrombosiscomprising administering to a mammal in need thereof a therapeuticallyeffective amount of a compound or salt of the invention.

In some aspects, the invention includes a method of treating thrombosismediated at least in part by BTK comprising administering to a mammal inneed thereof a therapeutically effective amount of a compound or salt ofFormula I.

In some aspects, the invention includes a method of treating or a methodof manufacturing a medicament for treating thrombosis, such as thosedescribed herein, which is mediated at least in part by BTK, comprisingadministering to a mammal in need thereof a therapeutically effectiveamount of a compound or salt of the invention.

In some aspects, the invention includes a method of treating cholestaticpruritus comprising administering to a mammal in need thereof atherapeutically effective amount of a compound or salt of the invention.

In some aspects, the invention includes a method of treating cholestaticpruritus mediated at least in part by BTK comprising administering to amammal in need thereof a therapeutically effective amount of a compoundor salt of Formula I.

In some aspects, the invention includes a method of treating or a methodof manufacturing a medicament for cholestatic pruritus, such as thosedescribed herein, which is mediated at least in part by BTK, comprisingadministering to a mammal in need thereof a therapeutically effectiveamount of a compound or salt of the invention.

The compounds of Formula I of the invention are useful in the treatmentof a variety of cancers, including, but not limited to, solid tumors,sarcoma, fibrosarcoma, osteoma, melanoma, retinoblastoma,rhabdomyosarcoma, glioblastoma, neuroblastoma, teratocarcinoma,hematopoietic malignancy, and malignant ascites. More specifically, thecancers include, but not limited to, lung cancer, bladder cancer,pancreatic cancer, kidney cancer, gastric cancer, breast cancer, coloncancer, prostate cancer (including bone metastases), hepatocellularcarcinoma, ovarian cancer, esophageal squamous cell carcinoma, melanoma,an anaplastic large cell lymphoma, an inflammatory myofibroblastictumor, and a glioblastoma.

In some aspects, the above methods are used to treat one or more ofbladder, colorectal, non-small cell lung, breast, or pancreatic cancer.In some aspects, the above methods are used to treat one or more ofovarian, gastric, head and neck, prostate, hepatocellular, renal,glioma, or sarcoma cancer.

In some aspects, the invention includes a method, including the abovemethods, wherein the compound is used to inhibit cellular epithelial tomesenchymal transition (EMT).

In some aspects, the method further comprises administering at least onadditional active agent. In some aspects, the invention includes amethod of treating cancer comprising administering to a mammal in needthereof a therapeutically effective amount of a compound or salt of theinvention, wherein at least one additional active anti-cancer agent isused as part of the method.

In some aspects, the invention includes a method of treating the diseasedescribed herein mediated at least in part by BTK comprisingadministering to a mammal in need thereof a therapeutically effectiveregimen comprising a compound or salt of Formula I and at least oneadditional active agent. Generally, dosage levels on the order of fromabout 0.01 mg/kg to about 150 mg/kg of body weight per day are useful inthe treatment of the above-indicated conditions, or alternatively about0.5 mg to about 7 g per patient per day. For example, inflammation,cancer, psoriasis, allergy/asthma, disease and conditions of the immunesystem, disease and conditions of the Central Nervous System (CNS), maybe effectively treated by the administration of from about 0.01 to 50 mgof the compound per kilogram of body weight per day, or alternativelyabout 0.5 mg to about 3.5 g per patient per day.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

GENERAL DEFINITIONS AND ABBREVIATIONS

Except where otherwise indicated, the following general conventions anddefinitions apply. Unless otherwise indicated herein, language and termsare to be given their broadest reasonable interpretation as understoodby the skilled artisan. Any examples given are nonlimiting.

Any section headings or subheadings herein are for the reader'sconvenience and/or formal compliance and are non-limiting.

A recitation of a compound herein is open to and embraces any materialor composition containing the recited compound (e.g., a compositioncontaining a racemic mixture, tautomers, epimers, stereoisomers, impuremixtures, etc.). In that a salt, solvate, or hydrate, polymorph, orother complex of a compound includes the compound itself, a recitationof a compound embraces materials containing such forms. Isotopicallylabeled compounds are also encompassed except where specificallyexcluded. For example, hydrogen is not limited to hydrogen containingzero neutrons. For example, deuterium is referred to herein as “D” andmeans a hydrogen atom having one neutron.

The term “active agent” means a compound of the invention in any salt,polymorph, crystal, solvate, or hydrated form.

The term “substituted” and substitutions contained in formulas hereinrefer to the replacement of one or more hydrogen radicals in a givenstructure with a specified radical, or, if not specified, to thereplacement with any chemically feasible radical. When more than oneposition in a given structure can be substituted with more than onesubstituent selected from specified groups, the substituents can beeither the same or different at every position (independently selected)unless otherwise indicated. In some cases, two positions in a givenstructure can be substituted with one shared substituent. It isunderstood that chemically impossible or highly unstable configurationsare not desired or intended, as the skilled artisan would appreciate.

In descriptions and claims where subject matter (e.g., substitution at agiven molecular position) is recited as being selected from a group ofpossibilities, the recitation is specifically intended to include anysubset of the recited group. In the case of multiple variable positionsor substituents, any combination of group or variable subsets is alsocontemplated. Unless indicated otherwise, a substituent, diradical orother group referred to herein can be bonded through any suitableposition to a referenced subject molecule. For example, the term“indolyl” includes 1-indolyl, 2-indolyl, 3-indolyl, etc.

The convention for describing the carbon content of certain moieties is“(C_(a-b))” or “C_(a)-C_(b)” meaning that the moiety can contain anynumber of from “a” to “b” carbon atoms. C₀alkyl means a single covalentchemical bond when it is a connecting moiety, and a hydrogen when it isa terminal moiety. Similarly, “x-y” can indicate a moiety containingfrom x to y atoms, e.g., ₅₋₆heterocycloalkyl means a heterocycloalkylhaving either five or six ring members. “C_(x-y)” may be used to definenumber of carbons in a group. For example, “C₀₋₁₂alkyl” means alkylhaving 0-12 carbons, wherein C₀alkyl means a single covalent chemicalbond when a linking group and means hydrogen when a terminal group.C₀₋₁₂alkyl includes various alternative embodiments, including, but notlimited to, C₁₋₁₂alkyl, C₂₋₁₂alkyl, C₃₋₁₂alkyl, C₄₋₁₂alkyl, C₅₋₁₂alkyl,C₆₋₁₂alkyl, C₇₋₁₂alkyl, C₈₋₁₂alkyl, C₉₋₁₂alkyl, C₁₀₋₁₂alkyl,C₁₁₋₁₂alkyl, C₁₋₁₁alkyl, C₁₋₁₀alkyl, C₁₋₉alkyl, C₁₋₈alkyl, C₁₋₇alkyl,C₁₋₆alkyl, C₁₋₅alkyl, C₁₋₄alkyl, C₁₋₃alkyl, C₁₋₂alkyl, C₁alkyl, andC₀alkyl. C₀₋₁₂alkyl further includes any combination of “a” and “b”and/or “x” and “y” number of carbon atoms including, but not limited to,C₂₋₁₂alkyl, C₃₋₁₁alkyl, C₄₋₁₀alkyl, C₅₋₉alkyl, C₆₋₈alkyl and C₇alkyl.

The term “absent,” as used herein to describe a structural variable(e.g., “—R— is absent”) means that diradical R has no atoms, and merelyrepresents a bond between other adjoining atoms, unless otherwiseindicated.

Unless otherwise indicated (such as by a connecting “-”), theconnections of compound name moieties are at the rightmost recitedmoiety. That is, the substituent name starts with a terminal moiety,continues with any bridging moieties, and ends with the connectingmoiety. For example, “heteroarylthioC₁₋₄alkyl” is a heteroaryl groupconnected through a thio sulfur to a C₁₋₄ alkyl, which alkyl connects tothe chemical species bearing the substituent.

The term “aliphatic” means any hydrocarbon moiety, and can containlinear, branched, and cyclic parts, and can be saturated or unsaturated.

The term “alkyl” means any saturated hydrocarbon group that isstraight-chain or branched. Examples of alkyl groups include methyl,ethyl, propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and thelike.

The term “alkenyl” means any ethylenically unsaturated straight-chain orbranched hydrocarbon group. Representative examples include, but are notlimited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, andthe like.

The term “alkynyl” means any acetylenically unsaturated straight-chainor branched hydrocarbon group. Representative examples include, but arenot limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl,and the like.

The term “alkoxy” means —O-alkyl, —O-alkenyl, or —O-alkynyl.“Haloalkoxy” means an —O-(haloalkyl) group. Representative examplesinclude, but are not limited to, trifluoromethoxy, tribromomethoxy, andthe like.

“Haloalkyl” means an alkyl, preferably lower alkyl, that is substitutedwith one or more same or different halo atoms.

“Hydroxyalkyl” means an alkyl, preferably lower alkyl, that issubstituted with one, two, or three hydroxy groups; e.g., hydroxymethyl,1 or 2-hydroxyethyl, 1,2-, 1,3-, or 2,3-dihydroxypropyl, and the like.

The term “alkanoyl” means —C(O)-alkyl, —C(O)-alkenyl, or —C(O)-alkynyl.

“Alkylthio” means an —S-(alkyl) or an —S-(unsubstituted cycloalkyl)group. Representative examples include, but are not limited to,methylthio, ethylthio, propylthio, butylthio, cyclopropylthio,cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.

The term “cyclic” means any ring system with or without heteroatoms (N,O, or S(O)₀₋₂), and which can be saturated, partially saturated, orunsaturated. Ring systems can be bridged and can include fused rings.The size of ring systems may be described using terminology such as“_(x-y)cyclic,” which means a cyclic ring system that can have from x toy ring atoms. For example, the term “₉₋₁₀carbocyclic” means a 5,6 or 6,6fused bicyclic carbocyclic ring system which can be saturated,unsaturated or aromatic. It also means a phenyl fused to one 5 or 6membered saturated or unsaturated carbocyclic group. Nonlimitingexamples of such groups include naphthyl, 1,2,3,4 tetrahydronaphthyl,indenyl, indanyl, and the like.

The term “carbocyclic” means a cyclic ring moiety containing only carbonatoms in the ring(s) without regard to aromaticity. A 3-10 memberedcarbocyclic means chemically feasible monocyclic and fused bicycliccarbocyclics having from 3 to 10 ring atoms. Similarly, a 4-6 memberedcarbocyclic means monocyclic carbocyclic ring moieties having 4 to 6ring carbons, and a 9-10 membered carbocyclic means fused bicycliccarbocyclic ring moieties having 9 to 10 ring carbons.

The term “cycloalkyl” means a non-aromatic 3-12 carbon mono-cyclic,bicyclic, or polycyclic aliphatic ring moiety. Cycloalkyl can bebicycloalkyl, polycycloalkyl, bridged, or spiroalkyl. One or more of therings may contain one or more double bonds but none of the rings has acompletely conjugated pi-electron system. Examples, without limitation,of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane,cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane,cycloheptatriene, and the like.

The term “unsaturated carbocyclic” means any cycloalkyl containing atleast one double or triple bond. The term “cycloalkenyl” means acycloalkyl having at least one double bond in the ring moiety.

The terms “bicycloalkyl” and “polycycloalkyl” mean a structureconsisting of two or more cycloalkyl moieties that have two or moreatoms in common. If the cycloalkyl moieties have exactly two atoms incommon they are said to be “fused”. Examples include, but are notlimited to, bicyclo[3.1.0]hexyl, perhydronaphthyl, and the like. If thecycloalkyl moieties have more than two atoms in common they are said tobe “bridged”. Examples include, but are not limited to,bicyclo[2.2.1]heptyl (“norbornyl”), bicyclo[2.2.2]octyl, and the like.

The term “spiroalkyl” means a structure consisting of two cycloalkylmoieties that have exactly one atom in common. Examples include, but arenot limited to, spiro[4.5]decyl, spiro[2.3]hexyl, and the like.

The term “aromatic” means a planar ring moieties containing 4n+2 pielectrons, wherein n is an integer.

The term “aryl” means aromatic moieties containing only carbon atoms inits ring system. Non-limiting examples include phenyl, naphthyl, andanthracenyl. The terms “aryl-alkyl” or “arylalkyl” or “aralkyl” refer toany alkyl that forms a bridging portion with a terminal aryl.

“Aralkyl” means alkyl that is substituted with an aryl group as definedabove; e.g., —CH₂ phenyl, —(CH₂)₂phenyl, —(CH₂)₃ phenyl,CH₃CH(CH₃)CH₂phenyl, and the like and derivatives thereof.

The term “heterocyclic” means a cyclic ring moiety containing at leastone heteroatom (N, O, or S(O)₀₋₂), including heteroaryl,heterocycloalkyl, including unsaturated heterocyclic rings.

The term “heterocycloalkyl” means a non-aromatic monocyclic, bicyclic,or polycyclic heterocyclic ring moiety of 3 to 12 ring atoms containingat least one ring having one or more heteroatoms. The rings may alsohave one or more double bonds. However, the rings do not have acompletely conjugated pi-electron system. Examples, without limitation,of heterocycloalkyl rings include azetidine, oxetane, tetrahydrofuran,tetrahydropyran, oxepane, oxocane, thietane, thiazolidine, oxazolidine,oxazetidine, pyrazolidine, isoxazolidine, isothiazolidine,tetrahydrothiophene, tetrahydrothiopyran, thiepane, thiocane, azetidine,pyrrolidine, piperidine, N-methylpiperidine, azepane, 1,4-diazapane,azocane, [1,3]dioxane, oxazolidine, piperazine, homopiperazine,morpholine, thiomorpholine, 1,2,3,6-tetrahydropyridine and the like.Other examples of heterocycloalkyl rings include the oxidized forms ofthe sulfur-containing rings. Thus, tetrahydrothiophene-1-oxide,tetrahydrothiophene-1,1-dioxide, thiomorpholine-1-oxide,thiomorpholine-1,1-dioxide, tetrahydrothiopyran-1-oxide,tetrahydrothiopyran-1,1-dioxide, thiazolidine-1-oxide, andthiazolidine-1,1-dioxide are also considered to be heterocycloalkylrings. The term “heterocycloalkyl” also includes fused ring systems andcan include a carbocyclic ring that is partially or fully unsaturated,such as a benzene ring, to form benzofused heterocycloalkyl rings. Forexample, 3,4-dihydro-1,4-benzodioxine, tetrahydroquinoline,tetrahydroisoquinoline and the like. The term “heterocycloalkyl” alsoincludes heterobicycloalkyl, heteropolycycloalkyl, or heterospiroalkyl,which are bicycloalkyl, polycycloalkyl, or spiroalkyl, in which one ormore carbon atom(s) are replaced by one or more heteroatoms selectedfrom O, N, and S. For example, 2-oxa-spiro[3.3]heptane,2,7-diaza-spiro[4.5]decane, 6-oxa-2-thia-spiro[3.4]octane,octahydropyrrolo[1,2-a]pyrazine, 7-azabicyclo[2.2.1]heptane,2-oxa-bicyclo[2.2.2]octane, and the like, are such heterocycloalkyls.

Examples of saturated heterocyclic groups include, but are not limitedto oxiranyl, thiaranyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl,1,4-oxathianyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathianyl,oxepanyl, thiepanyl, azepanyl, 1,4-dioxepanyl, 1,4-oxathiepanyl,1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thieazepanyl, 1,4-diazepanyl

Non-aryl heterocyclic groups include saturated and unsaturated systemsand can include groups having only 4 atoms in their ring system. Theheterocyclic groups include benzo-fused ring systems and ring systemssubstituted with one or more oxo moieties. Recitation of ring sulfur isunderstood to include the sulfide, sulfoxide or sulfone where feasible.The heterocyclic groups also include partially unsaturated or fullysaturated 4-10 membered ring systems, e.g., single rings of 4 to 8 atomsin size and bicyclic ring systems, including aromatic 6-membered aryl orheteroaryl rings fused to a non-aromatic ring. Also included are 4-6membered ring systems (“4-6 membered heterocyclic”), which include 5-6membered heteroaryls, and include groups such as azetidinyl andpiperidinyl. Heterocyclics can be heteroatom-attached where such ispossible. For instance, a group derived from pyrrole can be pyrrol-1-yl(N-attached) or pyrrol-3-yl (C-attached). Other heterocyclics includeimidazo(4,5-b)pyridin-3-yl and benzoimidazol-1-yl.

Examples of heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino,morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl,oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,3H-indolyl, quinolizinyl, and the like.

The term “unsaturated heterocyclic” means a heterocycloalkyl containingat least one unsaturated bond. The term “heterobicycloalkyl” means abicycloalkyl structure in which at least one carbon atom is replacedwith a heteroatom. The term “heterospiroalkyl” means a spiroalkylstructure in which at least one carbon atom is replaced with aheteroatom.

Examples of partially unsaturated heteroalicyclic groups include, butare not limited to: 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl,2H-pyranyl, 1,2,3,4-tetrahydropyridinyl, and1,2,5,6-tetrahydropyridinyl.

The terms “heteroaryl” or “hetaryl” mean a monocyclic, bicyclic, orpolycyclic aromatic heterocyclic ring moiety containing 5-12 atoms.Examples of such heteroaryl rings include, but are not limited to,furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl,tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.The terms “heteroaryl” also include heteroaryl rings with fusedcarbocyclic ring systems that are partially or fully unsaturated, suchas a benzene ring, to form a benzofused heteroaryl. For example,benzimidazole, benzoxazole, benzothiazole, benzofuran, quinoline,isoquinoline, quinoxaline, indazole, imidazo[1,2-a]pyridine,3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl, 2-methyl-2H-indazol-5-yl,3-methylimidazo[1,5-a]pyridine, 2-methyl-1H-benzo[d]imidazole,1H-pyrrolo[2,3-b]pyridine, 3,4-Dihydro-2H-benzo[b][1,4]oxazine,2-oxo-2,3-dihydrobenzo[d]oxazole,3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine,2,3-Dihydrobenzo[b][1,4]dioxine,2-methyl-[1,2,4]triazolo[1,5-a]pyridine, and the like. Furthermore, theterms “heteroaryl” include fused 5-6, 5-5, 6-6 ring systems, optionallypossessing one nitrogen atom at a ring junction. Examples of suchhetaryl rings include, but are not limited to, pyrrolopyrimidinyl,imidazo[1,2-a]pyridinyl, imidazo[2, 1-b]thiazolyl,imidazo[4,5-b]pyridine, pyrrolo[2,1-f][1,2,4]triazinyl, and the like.Heteroaryl groups may be attached to other groups through their carbonatoms or the heteroatom(s), if applicable. For example, pyrrole may beconnected at the nitrogen atom or at any of the carbon atoms.

Heteroaryls include, e.g., 5 and 6 membered monocyclics such aspyrazinyl and pyridinyl, and 9 and 10 membered fused bicyclic ringmoieties, such as quinolinyl. Other examples of heteroaryl includequinolin-4-yl, 7-methoxy-quinolin-4-yl, pyridin-4-yl, pyridin-3-yl, andpyridin-2-yl. Other examples of heteroaryl include pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl,pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl,benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl,pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl,thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, furopyridinyl, and the like. Examples of 5-6 memberedheteroaryls include, thiophenyl, isoxazolyl, 1,2,3-triazolyl,1,2,3-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-triazolyl,1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-oxadiazolyl,1,2,5-thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4oxadiazolyl, 1,2,5-triazinyl, 1,3,5-triazinyl,6-oxo-1,6-dihydropyridine, and the like.

“Heteroaralkyl” group means alkyl, preferably lower alkyl, that issubstituted with a heteroaryl group; e.g., —CH₂ pyridinyl,—(CH₂)₂pyrimidinyl, —(CH₂)₃imidazolyl, and the like, and derivativesthereof.

A pharmaceutically acceptable heteroaryl is one that is sufficientlystable to be attached to a compound of the invention, formulated into apharmaceutical composition and subsequently administered to a patient inneed thereof.

Examples of monocyclic heteroaryl groups include, but are not limitedto: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl,oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl,1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl,1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl,1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl tetrazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl.

Examples of fused ring heteroaryl groups include, but are not limitedto: benzoduranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl,benzotriazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl,pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl,imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl,pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3-c]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, isoindolyl,indazolyl, purinyl, indolinyl, imidazo[1,2-a]pyridinyl,imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,pyrrolo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, quinolinyl,isoquinolinyl, cinnolinyl, azaquinazoline, quinoxalinyl, phthalazinyl,1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl,1,5-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl,pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl,pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl,pyrimido[5,4-d]pyrimidinyl, pyrimido[2,3-b]pyrazinyl,pyrimido[4,5-d]pyrimidinyl.

“Arylthio” means an —S-aryl or an —S-heteroaryl group, as definedherein. Representative examples include, but are not limited to,phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio,and the like and derivatives thereof.

The term “9-10 membered heterocyclic” means a fused 5,6 or 6,6 bicyclicheterocyclic ring moiety, which can be saturadated, unsaturated oraromatic. The term “9-10 membered fused bicyclic heterocyclic” alsomeans a phenyl fused to one 5 or 6 membered heterocyclic group. Examplesinclude benzofuranyl, benzothiophenyl, indolyl, benzoxazolyl,3H-imidazo[4,5-c]pyridin-yl, dihydrophthazinyl,1H-imidazo[4,5-c]pyridin-1-yl, imidazo[4,5-b]pyridyl, 1,3benzo[1,3]dioxolyl, 2H-chromanyl, isochromanyl, 5-oxo-2,3dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidyl, 1,3-benzothiazolyl, 1,4,5,6tetrahydropyridazyl, 1,2,3,4,7,8hexahydropteridinyl,2-thioxo-2,3,6,9-tetrahydro-1H-purin-8-yl, 3,7-dihydro-1H-purin-8-yl,3,4-dihydropyrimidin-1-yl, 2,3-dihydro-1,4-benzodioxinyl,benzo[1,3]dioxolyl, 2H-chromenyl, chromanyl, 3,4-dihydrophthalazinyl,2,3-ihydro-1H-indolyl, 1,3-dihydro-2H-isoindol-2-yl,2,4,7-trioxo-1,2,3,4,7,8-hexahydropteridin-yl, thieno[3,2-d]pyrimidinyl,4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-yl,1,3-dimethyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1H-purinyl,1,2-dihydroisoquinolinyl, 2-oxo-1,3-benzoxazolyl,2,3-dihydro-5H-1,3-thiazolo-[3,2-a]pyrimidinyl,5,6,7,8-tetrahydro-quinazolinyl, 4-oxochromanyl, 1,3-benzothiazolyl,benzimidazolyl, benzotriazolyl, purinyl, furylpyridyl,thiophenylpyrimidyl, thiophenylpyridyl, pyrrolylpiridyl,oxazolylpyridyl, thiazolylpiridyl, 3,4-dihydropyrimidin-1-ylimidazolylpyridyl, quinoliyl, isoquinolinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pyrazolyl[3,4]pyridine, 1,2-dihydroisoquinolinyl,cinnolinyl, 2,3-dihydro-benzo[1,4]dioxin4-yl,4,5,6,7-tetrahydro-benzo[b]-thiophenyl-2-yl, 1,8-naphthyridinyl,1,5-napthyridinyl, 1,6-naphthyridinyl, 1,7-napthyridinyl,3,4-dihydro-2H-1,4-benzothiazine, 4,8-dihydroxy-quinolinyl,1-oxo-1,2-dihydro-isoquinolinyl, 4-phenyl-[1,2,3]thiadiazolyl, and thelike.

The term “aryloxy” means an —O-aryl or an —O-heteroaryl group, asdefined herein. Representative examples include, but are not limited to,phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy,pyrazinyloxy, and the like, and derivatives thereof.

The term “oxo” means a compound containing a carbonyl group. One in theart understands that an “oxo” requires a second bond from the atom towhich the oxo is attached.

The term “halo” or “halogen” means fluoro, chloro, bromo, or iodo.

“Acyl” means a —C(O)R group, where R can be selected from thenonlimiting group of hydrogen or optionally substituted lower alkyl,trihalomethyl, unsubstituted cycloalkyl, aryl, or other suitablesubstituent.

“Thioacyl” or “thiocarbonyl” means a —C(S)R″ group, with R as definedabove.

The term “protecting group” means a suitable chemical group that can beattached to a functional group and removed at a later stage to revealthe intact functional group. Examples of suitable protecting groups forvarious functional groups are described in T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 2d Ed., John Wiley andSons (1991 and later editions); L. Fieser and M. Fieser, Fieser andFieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); andL. Paquette, ed. Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995). The term “hydroxy protecting group”, as usedherein, unless otherwise indicated, includes Ac, CBZ, and varioushydroxy protecting groups familiar to those skilled in the art includingthe groups referred to in Greene.

The term “linear structure” means a moiety having substituents that donot cyclize to form a ring system. A representative example includes,but is not limited to, a compound including —NR^(X)R^(Y) where any atomsof “R^(X)” and any atoms of “R^(Y)” do not connect to form a ring.

As used herein, the term “pharmaceutically acceptable salt” means thosesalts which retain the biological effectiveness and properties of theparent compound and do not present safety or toxicity issues. The term“pharmaceutically acceptable salt(s)” is known in the art and includessalts of acidic or basic groups which can be present in the compoundsand prepared or resulting from pharmaceutically acceptable bases oracids.

The term “pharmaceutical composition” means an active compound in anyform suitable for effective administration to a subject, e.g., a mixtureof the compound and at least one pharmaceutically acceptable carrier.

As used herein, a “physiologically/pharmaceutically acceptable carrier”means a carrier or diluent that does not cause significant irritation toan organism and does not abrogate the biological activity and propertiesof the administered compound.

A “pharmaceutically acceptable excipient” means an inert substance addedto a pharmaceutical composition to further facilitate administration ofa compound. Examples, without limitation, of excipients include calciumcarbonate, calcium phosphate, various sugars and types of starch,cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

The terms “treat,” “treatment,” and “treating” means reversing,alleviating, inhibiting the progress of, or partially or completelypreventing the disorder or condition to which such term applies, or oneor more symptoms of such disorder or condition. “Preventing” meanstreating before an infection occurs.

“Therapeutically effective amount” means that amount of the compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disorder being treated, or result in inhibition of theprogress or at least partial reversal of the condition.

NMR Nuclear magnetic resonance

MDP(S) Mass-directed HPLC purification (system)

LC/MS Liquid chromatography mass spectrometry

LDA Lithium diisopropylamide

tert-BuOH tert-Butanol

AcOH Acetic acid

CDI 1,1′-Carbonyldiimidazole

DCE 1,1-Dichloroethane

DCM Dichloromethane

DMF Dimethylformamide

THF Tetrahydrofuran

MeOH Methanol

EtOH Ethanol

EtOAc Ethyl acetate

MeCN Acetonitrile

DMSO Dimethylsulfoxide

Boc tert-Butyloxycarbonyl

DME 1,2-Dimethoxyethane

DMF N,N-Dimethylformamide

DIPEA/DIEA Diisopropylethylamine

PS-DIEA Polymer-supported diisopropylethylamine

PS-PPh₃-Pd Polymer-supported Pd(PPh₃)₄

LAH Lithium aluminum hydride

EDC 1-(3-Dimethylaminopropyl)-3-ethyl carbodiimide

HATU:1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide

hexafluorophosphate

HOBt 1-Hydroxybenzotnazole

DMAP 4-Dimethylaminopyridine

SEM-Cl 2-(Trimethylsilyl)ethoxymethyl chloride

TBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate

TEMPO 2,2,6,6-Tetramethylpiperidine-1-oxyl

TFA (A) Trifluoroacetic acid (anhydride)

TLC Thin layer chromatography

TMSCN Trimethylsilyl cyanide

Min Minute(s)

NMO N-Methylmorpholine N-oxide

h Hour(s)

d Day(s)

RT, R.T., r.t., r.t or rt Room temperature

t_(R) Retention time

Conc. Concentrated

What is claimed is:
 1. A compound having a Formula IId′, or apharmaceutically acceptable salt or solvate thereof:

wherein X is

Z is CH or N; G¹, G², and G³ are H, or optionally substituted with oneor more substituents independently selected from the group consisting ofD (deuterium), C₁₋₁₂ alkyl, halogen, CN, and CF₃; R² and R³ are eachindependently selected from the group consisting of H, D, C₁₋₁₂ alkyl,halogen, CN, and CF₃, wherein C₁₋₁₂ alkyl is optionally substituted withNR¹¹R¹²; R⁴ is selected from the group consisting of H, D, C₁₋₁₂ alkyl,halogen, CN, and CF₃; and R¹¹ and R¹² are independently H or C₁₋₆ alkyl.2. The compound according to claim 1, wherein wherein X is


3. The compound according to claim 1, wherein G¹, G², and G³ are H, oroptionally substituted with one or more halogen.
 4. The compoundaccording to claim 1, wherein R² and R³ are H or C₁₋₁₂ alkyl, whereinC₁₋₁₂ alkyl is optionally substituted with NR¹¹R¹², and R¹¹ and R¹² areH or CH₃.
 5. The compound according to claim 1, which is


6. The compound according to claim 1, which is


7. The compound according to claim 1, which is


8. The compound according to claim 1, which is